Journal Article

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

Pasquinelli, Virginia, García, Verónica E, Hernández Del Pino, Rodrigo E, Rolandelli, Agustín, Rovetta, Ana I, Pellegrini, Joaquín M, Malbran, Alejandro, Peña, Delfina, Palmero, Domingo J, Álvarez, Guadalupe I, Musella, Rosa M

2017

Overview

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.

• Publisher: Nature Publishing Group,Blackwell Science Ltd
• Subject: Adaptive immunity / Adult / Antigens / Apoptosis / CD25 antigen / Cell activation / Cell Death / Cell Differentiation / Cells, Cultured / Contraction / FasL protein / Female / Homeostasis / Humans / Immunity / Immunosuppression / Interferon-gamma - metabolism / Interleukin 17 / Interleukin 2 / Interleukin-17 - metabolism / Kinases / Lymphocyte Activation / Lymphocytes B / Lymphocytes T / Male / Mycobacterium tuberculosis - immunology / Neoplasm Proteins - metabolism / Phenotypes / Phosphorylation / Protein-Tyrosine Kinases - metabolism / SAP protein / Signal Transduction / Signaling Lymphocytic Activation Molecule Family - metabolism / T cell receptors / Th2 Cells - immunology / Tuberculosis / Tuberculosis - immunology / γ-Interferon