Protective immunity against Mycobacterium tuberculosis (Mtb) requires IFNG. Besides, IFNG-mediated induction of autophagy suppresses survival of virulent Mtb in macrophage cell lines. We investigated the contribution of autophagy to the defense against Mtb antigen (Mtb-Ag) in cells from tuberculosis patients and healthy donors (HD). Patients were classified as high responders (HR) if their T cells produced significant IFNG against Mtb-Ag; and low responders (LR) when patients showed weak or no T cell responses to Mtb-Ag. The highest autophagy levels were detected in HD cells whereas the lowest quantities were observed in LR patients. Interestingly, upon Mtb-Ag stimulation, we detected a positive correlation between IFNG and MAP1LC3B-II/LC3-II levels. Actually, blockage of Mtb-Ag-induced IFNG markedly reduced autophagy in HR patients whereas addition of limited amounts of IFNG significantly increased autophagy in LR patients. Therefore, autophagy collaborates with human immune responses against Mtb in close association with specific IFNG secreted against the pathogen.

Mycobacterium tuberculosis (Mtb) causes nearly 10 millions of new tuberculosis disease cases annually. However, most individuals exposed to Mtb do not develop tuberculosis, suggesting the influence of a human genetic component. Here, we investigated the association of the rs2275913 SNP (G → A) from IL-17A and tuberculosis in Argentina by a case-control study. Furthermore, we evaluated in vitro the functional relevance of this SNP during the immune response of the host against Mtb and analyzed its impact on clinical parameters of the disease. We found an association between the AA genotype and tuberculosis resistance. Additionally, within the healthy donors population, AA cells stimulated with a Mtb lysate (Mtb-Ag) produced the highest amounts of IL-17A and IFN-γ, which further support the genetic evidence found. In contrast, within the tuberculosis patients population, AA Mtb-Ag stimulated cells showed the lowest immunological parameters and we evidenced an association between the AA genotype and clinical parameters of disease severity, such as severe radiological lesions and higher bacilli burden in sputum. Overall, our findings demonstrated that the AA genotype from the IL-17A rs2275913 SNP is positively associated with protection to active tuberculosis but related to higher disease severity in the Argentinean population.

• Stimulation with Rv2626c M. tuberculosis antigen induced differential amounts of IFN-γ in LTBI individuals as compared to HD. • The cumulative response to specific Rv2626c-derived peptide pools improved the discrimination of LTBI individuals from HD. • PBMC or whole blood stimulation with Rv2626c differentiated latent from active infection (LTBI from TB patients).

Production of IFN‐γ contributes to host defense against Mycobacterium tuberculosis (Mtb) infection. We previously demonstrated that Signaling lymphocytic activation molecule‐associated protein (SAP) expression on cells from tuberculosis (TB) patients was inversely correlated with IFN‐γ production. Here we first investigated the role of NK, T‐ and B‐cell antigen (NTB‐A)/SAP pathway in the regulation of Th1 response against Mtb. Upon antigen stimulation, NTB‐A phosphorylation rapidly increases and afterwards modulates IFN‐γ and IL‐17 secretion. To sustain a healthy immune system, controlled expansion and contraction of lymphocytes, both during and after an adaptive immune response, is essential. Besides, restimulation‐induced cell death (RICD) results in an essential homeostatic mechanism for precluding excess T‐cell accumulation and associated immunopathology during the course of certain infections. Accordingly, we found that the NTB‐A/SAP pathway was required for RICD during active tuberculosis. In low responder (LR) TB patients, impaired RICD was associated with diminished FASL levels, IL‐2 production and CD25^high expression after cell‐restimulation. Interestingly, we next observed that SAP mediated the recruitment of the Src‐related kinase FYNT, only in T cells from LR TB patients that were resistant to RICD. Together, we showed that the NTB‐A/SAP pathway regulates T‐cell activation and RICD during human TB. Moreover, the NTB‐A/SAP/FYNT axis promotes polarization to an unfavorable Th2‐phenotype.