Mycobacterium tuberculosis Cell Wall Glycolipids Directly Inhibit CD4+ T-Cell Activation by Interfering with Proximal T-Cell-Receptor Signaling

RN Mahon, RE Rojas, SA Fulton, JL Franko… - Infection and …, 2009 - Am Soc Microbiol
RN Mahon, RE Rojas, SA Fulton, JL Franko, CV Harding, WH Boom
Infection and immunity, 2009Am Soc Microbiol
Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust
adaptive CD4+ T-cell responses. We have previously shown that M. tuberculosis can
indirectly inhibit CD4+ T cells by suppressing the major histocompatibility complex class II
antigen-presenting cell function of macrophages. This study was undertaken to determine if
M. tuberculosis could directly inhibit CD4+ T-cell activation. Murine CD4+ T cells were
purified from spleens by negative immunoaffinity selection followed by flow sorting. Purified …
Abstract
Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust adaptive CD4+ T-cell responses. We have previously shown that M. tuberculosis can indirectly inhibit CD4+ T cells by suppressing the major histocompatibility complex class II antigen-presenting cell function of macrophages. This study was undertaken to determine if M. tuberculosis could directly inhibit CD4+ T-cell activation. Murine CD4+ T cells were purified from spleens by negative immunoaffinity selection followed by flow sorting. Purified CD4+ T cells were activated for 16 to 48 h with CD3 and CD28 monoclonal antibodies in the presence or absence of M. tuberculosis and its subcellular fractions. CD4+ T-cell activation was measured by interleukin 2 production, proliferation, and expression of activation markers, all of which were decreased in the presence of M. tuberculosis. Fractionation identified that M. tuberculosis cell wall glycolipids, specifically, phosphatidylinositol mannoside and mannose-capped lipoarabinomannan, were potent inhibitors. Glycolipid-mediated inhibition was not dependent on Toll-like receptor signaling and could be bypassed through stimulation with phorbol 12-myristate 13-acetate and ionomycin. ZAP-70 phosphorylation was decreased in the presence of M. tuberculosis glycolipids, indicating that M. tuberculosis glycolipids directly inhibited CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling.
American Society for Microbiology