IFNγ-producing CD4 + T lymphocytes: the double-edged swords in tuberculosis

IFNγ-producing CD4 + T cells (IFNγ + CD4 + T cells) are the key orchestrators of protective immunity against Mycobacterium tuberculosis ( Mtb ). Primarily, these cells act by enabling Mtb -infected macrophages to enforce phagosome-lysosome fusion, produce reactive nitrogen intermediates (RNIs), and activate autophagy pathways. However, TB is a heterogeneous disease and a host of clinical and experimental findings has also implicated IFNγ + CD4 + T cells in TB pathogenesis. High frequency of IFNγ + CD4 + T cells is the most invariable feature of the active disease. Active TB patients mount a heightened IFNγ + CD4 + T cell response to mycobacterial antigens and demonstrate an IFNγ-inducible transcriptomic signature. IFNγ + CD4 + T cells have also been shown to mediate TB-associated immune reconstitution inflammatory syndrome (TB–IRIS) observed in a subset of antiretroviral therapy (ART)-treated HIV- and Mtb -coinfected people. The pathological face of IFNγ + CD4 + T cells during mycobacterial infection is further uncovered by studies in the animal model of TB–IRIS and in Mtb -infected PD-1 −/− mice. This manuscript encompasses the evidence supporting the dual role of IFNγ + CD4 + T cells during Mtb infection and sheds light on immune mechanisms involved in protection versus pathogenesis.