In conclusion, homozygosity for the catalytically inactive P1104A missense variant of <i>TYK2</i> selectively disrupts the induction of IFN-γ by IL-23 and is a common monogenic etiology of tuberculosis.
Mycobacterium tuberculosis multi-drug-resistant strain M induces IL-17<sup>+</sup> IFNγ<sup>-</sup> CD4<sup>+</sup> T cell expansion through an IL-23 and TGF-β-dependent mechanism in patients with MDR-TB tuberculosis.
To test this hypothesis, mechanistic studies were performed to examine whether and how tuberculosis blocked interleukin 23 (IL-23) and interleukin 2 (IL-2) signaling effects on a major human γδ T-cell subpopulation, phosphoantigen HMBPP-specific Vγ2Vδ2 T cells.
Accordingly, BCG-induced Th17-cell responses precede the generation of Th1-cell responses in vivo, whereas the absence of the IL-23 pathway decreases BCG vaccine-induced Th17 and Th1-cell immunity and subsequent vaccine-induced protection upon M. tuberculosis challenge.
By analyzing the cellular responses to mycobacterial antigens in patients who had latent tuberculosis with or without filarial infection, we were able to demonstrate that filarial infection coincident with M. tuberculosis infection significantly diminishes M. tuberculosis-specific Th1 (interleukin [IL]-12 and IFN-gamma) and type 17 T helper (Th17; IL-23 and IL-17) responses related to increased expression of cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1.
Our findings thus suggest an important role for IL-23 in human host responses to pulmonary infection with M. tuberculosis, and are consistent with epidemiologic and genetic studies that imply that H37Rv may not have unusual capacity to cause human disease.
Coimmunization of C57BL/6 mice with DNA expressing M. tuberculosis antigen 85B (Ag85B; DNA85B) and plasmids expressing IL-23 or IL-12 stimulated stronger Ag85B-specific T-cell proliferative and IFN-gamma responses than DNA85B alone, whereas the addition of p2AIL-27 had no effect.
This genetic variation may predispose individuals to tuberculosis infection by diminishing receptor responsiveness to IL-12 and to IL-23, leading to partial dysfunction of interferon-gamma-mediated immunity.