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.