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

Abstract

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.

Keywords: CD4+ T cell; Granuloma; IFN-gamma; Macrophage; Matrix metalloproteinase; Necrosis; Neutrophil; Pathogenesis; Protection; TB–IRIS; Tuberculosis.

Fig. 1

Protective versus pathological role of IFNγ⁺CD4⁺ T cells during Mycobacterium tuberculosis (Mtb) infection. Mtb exposure in most young children and immunodeficient people evokes a hypoactive IFNγ⁺CD4⁺ T cell response, which is inefficient in containing the bacilli. Therefore, Mtb infection in these people results in primary TB, frequently affecting the extrapulmonary sites. In contrast, most of the immunocompetent adults mount a balanced immune response to Mtb and contain it in the form of latent TB. With the course of time, IFNγ⁺CD4⁺ T cell response would aggravate in nearly 10% of latently infected people, leading to the development of active TB in them. Similar aggravation of IFNγ⁺CD4⁺ T cells is to blame for TB–IRIS development in a subset of ART-treated, HIV- and Mtb-coinfected people