Figure 4

Mechanisms by which deficiency or excess CD4⁺IFNγ⁺ T cells predispose to TB. (A) Deficiency of T_H1 (CD4⁺IFNγ⁺) T cells – as seen in advanced AIDS, genetic defects in the IFNγ-IL-12 axis, and in animal models – has been shown to increase the risk of TB and other mycobacterial infections. This IFNγ deficiency leads to an increase in IL-17 and neutrophilic influx. This combined with a lack of macrophage activation (due to insufficient number of CD4⁺IFNγ⁺ T cells) leads to an overwhelming Mtb infection of phagocytes, resulting in an unprotective, necrotic granuloma. (B) Excess T_H1 cell activation and numbers lead to a secondary increase in TNF, which can then induce RIP1 and RIP3 activation, excessive ROS formation, and macrophage necroptosis. The sequence of these events leads to over-inflamed, necrotic, and unprotective granulomas. (C) There is ample evidence in both humans and experimental animal models that optimal quantity and temporal influx of Mtb-specific CD4⁺IFNγ⁺ T cells are necessary for control ± eradication of Mtb infection, in part through activation of macrophages. IFNγ also inhibits IL-17 production from T_H17 cells which can induce chemokines for CD4⁺IFNγ⁺ T cells. In non-hematopoietic cells, IFNγ also induces IDO-1 production that inhibit excessive IL-17 production (via the catabolized products of tryptophan by the actions of IDO). Hence, IL-17 production is kept in check, limiting the amount of potentially harmful neutrophilic influx. IDO-1, indoleamine 2,3-dioxygenase; IFNγ, interferon-gamma; IL-12, interleukin-12; IL-17, interleukin-17; Mtb, Mycobacterium tuberculosis; RIP, receptor-interacting serine-threonine kinases; ROS, reactive oxygen species; TB, tuberculosis; TNF, tumor necrosis factor.