Inborn errors of immunity underlying defective T-cell memory

Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.Purpose of reviewT-cell memory is a complex process not well understood involving specific steps, pathways and different T-cell subpopulations. Inborn errors of immunity (IEIs) represent unique models to decipher some of these requirements in humans. More than 500 different IEIs have been reported to date, and recently a subgroup of monogenic disorders characterized by memory T-cell defects has emerged, providing novel insights into the pathways of T-cell memory generation and maintenance, although this new knowledge is mostly restricted to peripheral blood T-cell memory populations.This review draws up an inventory of the main and recent IEIs associated with T-cell memory defects and their mice models, with a particular focus on the nuclear factor kappa B (NF-kappa B) signalling pathway, including the scaffold protein capping protein regulator and myosin 1 linker 2 (CARMIL2) and the T-cell co-stimulatory molecules CD28 and OX-40. Besides NF-kappa B, IKZF1 (IKAROS), a key transcription factor of haematopoiesis and STAT3-dependent interleukin-6 signals involving the transcription factor ZNF341 also appear to be important for the generation of T cell memory. Somatic reversion mosaicism in memory T cells is documented for several gene defects supporting the critical role of these factors in the development of memory T cells with a potential clinical benefit.Systematic examination of T-cell memory subsets could be helpful in the diagnosis of IEIs.Papers of particular interest, published within the annual period of review, have been highlighted as:T-cell memory is a hallmark of adaptive immunity allowing to elicit faster and highly specific responses upon antigen recall. Establishment of T-cell memory is a complex process not well understood with specific steps and particular metabolic and epigenetic requirements [1-3]. Memory T-cells are heterogeneous including recirculating subsets in blood and lymphoid organs, while tissue resident memory T cells (TRM) represent the predominant T cell subpopulation that populate every organ and tissues. Circulating memory T cells are only a minor fraction (2-2.5%) of total memory T cells [3]. T-cell subpopulations with innate-like properties that differ from so-called 'conventional' T cells can be also considered as memory T-cell subsets based on their function and memory phenotype, such as the mucosal-associated invariant T cells (MAIT) and invariant NKT cells [4,5]. In addition, the T cell memory compartment could include functionally differentiated T-cell subsets such as T helper cells (Th1, Th2, Th17, Tfh) or induced T regulatory cells (Treg) that largely express memory markers. no caption availablePeripheral memory T cells detected in human blood are functionally and phenotypically divided in two major subsets: the central memory (TCM) and the effector memory (TEM) (Table 1). These two populations are distinguished based on expression of the cell surface markers CD45RA (or CD45RO), CCR7 (or CD62L). TCM and TEM correspond to (CD45RO+) CD45RA-/CCR7+ (CD62L+) and (CD45RO+) CD45RA-/CCR7- (CD62L-), respectively. TCM exhibit lymphoid organ homing phenotype (due to the expression of CCR7 and CD62L) and have high proliferative capabilities. In contrast, TEM are defined by limited proliferation potential, but immediate effector functions including cytokines production or cytotoxicity. A rare subset of memory T cells with a high proliferative self-renewal capacity has been also identified in human blood as stem-cell memory T cells (TSCM). Finally, terminally differentiated effector T cells (TEMRA) form a memory T cell subset that accumulates in blood of individuals with persistent infection, characterized by surface expression markers CD45RA+/CCR7- and often an exhausted phenotype. However, developmental relationships between these different subsets and their phenotypic and functional correspondence are still debated. Research on T-cell memory principally hinges on mouse studies, whereas human studies are limited due to restricted access to tissue samples.Blood memory T cell subsetsInborn errors of immunity (IEIs) in humans represent unique models to study immune responses in humans, with more than 500 different IEIs reported so far [6]. A subgroup of monogenic immune disorders characterized by defects in memory T cells has progressively emerged, thus providing insights into the mechanisms of T-cell memory generation and maintenance in humans, although this new knowledge is mostly limited to peripheral blood T-cell memory populations. Furthermore, status of memory T cells is not known in a substantial number of IEIs.Most of the genetic defects affecting components of the T cell receptor (TCR) signalling cascade causes severe combined immunodeficiency (SCID) or combined immunodeficiency (CID) characterized by low or normal numbers of T cells with altered functions [7]. These defects are often associated with reduced thymic output characterized by reduced counts of blood T cell thymic emigrants and decreased TRECs, progressive loss of naive T cells and T-cell lymphopenia at the expense of memory T cells with a high proportion of TEMRA. As such, decreased naive T cells exemplified by skewed ratio between naive and memory T cells in blood is considered as a hallmark of an underlying T-cell defect. However, there is a growing number of monogenic CIDs characterized by deficient T-cell responses associated with decreased, absence, or an abnormal phenotype of circulating memory T cells reflecting T-cell memory impairment. These defects frequently go along with inflated proportions of naive T lymphocytes and abnormalities in other T cell populations including MAIT cells and/or Th helper subpopulations. This review draws up an inventory of IEIs associated with T-cell memory defects and the underlying pathways. Clinical features and T cell defects of IEIs discussed herein are summarized in Table 2.Inborn errors of immunity (IEI) with defective T-cell memoryAD, autosomal dominant; AR, autosomal recessive; CID, combined immunodeficiency; CMC, chronic mucocutaneous candidiasis; CMV, cytomegalovirus; CVID, common variable immunodeficiency; DN, dominant negative; EBV, Epstein-Barr virus; EDA, ectodermal dysplasia and anhidrosis; ENT, ears; throat and nose; HHV8, human herpes virus 8; HI, haplo-insufficiency; HIES, hyper-IgE syndrome; HMG, hepatomegaly; HPV, human papillomaviruses; HyperIgE, high-serum Immunoglobulin E; IBD, inflammatory bowel disease; ILC, innate lymphocytes; LP, lymphoproliferation; MAIT, mucosal-associated invariant T; NEMO, NF-kappa B essential modulator; NK, natural killer; RTI, respiratory tract infections; SCID, severe combined immunodeficiency; SMG, splenomegaly; Tfh, T-follicular helper; Th, T helper; Treg, regulatory T; XL, X-linked.Broad nasal bridge, hyperextensible joints, osteoporosis and bone fractures, scoliosis, retained primary teeth; coronary and cerebral aneurysms.