Postnatal Expansion, Maturation, And Functionality Of Mr1t Cells In Humans

MR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR alpha-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, includingMycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labeling and of the TRAV1-2(+)MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2(+)CD161(++)CD26(++)cells). We analyzed postnatal expansion, maturation, and functionality of peripheral blood MR1-5-OP-RU tetramer(+)MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection withM. tuberculosis. Early after birth, frequencies of MR1-5-OP-RU tetramer(+)MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4(+)and TRAV1-2(-)population in neonates, to a predominantly TRAV1-2(+)CD161(++)CD26(++)CD8(+)population. We also observed that tetramer(+)MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased similar to 10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer(+)TRAV1-2(+)and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naive T cell markers on tetramer(+)TRAV1-2(+)MR1T cells more rapidly than tetramer(+)TRAV1-2(-)MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer(+)TRAV1-2(+)population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood.