Mycobacterium tuberculosis cell wall glycolipids directly inhibit CD4+ T-cell activation by interfering with proximal T-cell-receptor signaling.
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.
Mahon
Robert N
RN
Division of Infectious Diseases, Department of Medicine, Case Western Reserve University and University Hospitals, Case Medical Center, 10900 Euclid Avenue, BRB 1010B, Cleveland, OH 44106-4984, USA. rnm4@case.edu
Rojas
Roxana E
RE
Fulton
Scott A
SA
Franko
Jennifer L
JL
Harding
Clifford V
CV
Boom
W Henry
WH
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002473:Cell Wall / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D006017:Glycolipids / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology
D006017:Glycolipids; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell