Restimulation‐induced T‐cell death through NTB‐A/SAP signaling pathway is impaired in tuberculosis patients with depressed immune responses

Abstract

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 CD25high 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.

FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression

“…Work from our group and others has illuminated a central role for SAP/SLAM receptor signaling in governing RICD sensitivity in T cells [10, 11, 13]. Our results further underscore the importance of SAP-driven signaling in this process, demonstrating that Tregs have evolved to disable this signaling pathway via FOXP3-dependent SAP repression to resist RICD.…”

“…XLP-1 patients harbor null mutations in the signaling adaptor SLAM-associated protein (SAP), which is required for RICD [9, 10]. Indeed, work from our lab and others has shown that SAP associates with the signaling lymphocyte activation molecule (SLAM) family receptor NTB-A to potentiate TCR signal strength by displacing SHP-1 and recruiting LCK instead of FYN, which facilitates downstream signaling for apoptosis after TCR re-engagement [11-13]. SAP also represses DGKα to maintain a sufficient pool of diacylglycerol for robust TCR signaling [7, 14], further highlighting SAP as a central player in promoting RICD of effector T cells.…”

The Non-synonymous rs763780 Single-Nucleotide Polymorphism in IL17F Gene Is Associated With Susceptibility to Tuberculosis and Advanced Disease Severity in Argentina

“…Previously we showed that immunological attributes matched clinical parameters studied in TB in Argentina (6, 16, 43). Thus, we next decided to analyze whether there was a relationship between clinical parameters commonly studied in tuberculosis and the genetic variants of the rs763780 SNP.…”

“…We observed the maximum proportion of patients carrying the C variant in the LR subpopulation, individuals that display the most severe tuberculosis. We have previously reported that HR patients had significantly higher percentages of total lymphocytes and exhibited higher PPD diameters compared to LR patients; and that LR individuals had severe pulmonary lesions and a striking loss of weight compared to HR subjects (6, 16, 43). Surprisingly, by evaluating clinical parameters usually studied in tuberculosis, we did not find significant differences in the radiological pulmonary lesions of the patients carrying the different genotypes of the rs763780 SNP.…”

“…By using immunological parameters, we previously differentiated two populations of TB in Argentina, High, and Low Responders (HR and LR, respectively), where LR subjects suffer the most advanced disease (6, 16, 43). In order to further investigate whether subjects with a more effective immune response against Mtb displayed higher IL17F production, we analyzed the secretion of this cytokine by HR and LR TB.…”