Mycobacterium tuberculosis ManLAM inhibits T-cell-receptor signaling by interference with ZAP-70, Lck and LAT phosphorylation

Immune evasion is required for Mycobacterium tuberculosis to survive in the face of robust CD4+ T cell responses. We have shown previously that M. tuberculosis cell wall glycolipids, including mannose capped lipoarabinomannan (ManLAM), directly inhibit polyclonal murine CD4+ T cell activation by blocking ZAP-70 phosphorylation. We extended these studies to antigen-specific murine CD4+ T cells and primary human T cells and found that ManLAM inhibited them as well. Lck and LAT phosphorylation also were inhibited by ManLAM without affecting their localization to lipid rafts. Inhibition of proximal TCR signaling was temperature sensitive, suggesting that ManLAM insertion into T cell membranes was required. Thus, M. tuberculosis ManLAM inhibits antigen-specific CD4+ T cell activation by interfering with very early events in TCR signaling through ManLAM’s insertion in T cell membranes.

► ManLAM directly inhibits both monoclonal and polyclonal T cell activation.
► ManLAM inhibits entire proximal T-cell receptor signaling pathway.
► Inhibition of proximal T-cell receptor signaling is temperature sensitive.
► ManLAM inserts into lipid rafts of T-hybridoma cells.
► Insertion of ManLAM does not affect Lck or LAT’s presence in lipid raft.