<i>Mycobacterium tuberculosis</i> Membrane Vesicles Inhibit T Cell Activation

Abstract

<i>Mycobacterium tuberculosis</i> utilizes multiple mechanisms to evade host immune responses, and inhibition of effector CD4⁺ T cell responses by <i>M. tuberculosis</i> may contribute to immune evasion. TCR signaling is inhibited by <i>M. tuberculosis</i> cell envelope lipoglycans, such as lipoarabinomannan and lipomannan, but a mechanism for lipoglycans to traffic from <i>M. tuberculosis</i> within infected macrophages to reach T cells is unknown. In these studies, we found that membrane vesicles produced by <i>M. tuberculosis</i> and released from infected macrophages inhibited the activation of CD4⁺ T cells, as indicated by reduced production of IL-2 and reduced T cell proliferation. Flow cytometry and Western blot demonstrated that lipoglycans from <i>M. tuberculosis</i>-derived bacterial vesicles (BVs) are transferred to T cells, where they inhibit T cell responses. Stimulation of CD4⁺ T cells in the presence of BVs induced expression of GRAIL, a marker of T cell anergy; upon restimulation, these T cells showed reduced ability to proliferate, confirming a state of T cell anergy. Furthermore, lipoarabinomannan was associated with T cells after their incubation with infected macrophages in vitro and when T cells were isolated from lungs of <i>M. tuberculosis</i>-infected mice, confirming the occurrence of lipoarabinomannan trafficking to T cells in vivo. These studies demonstrate a novel mechanism for the direct regulation of CD4⁺ T cells by <i>M. tuberculosis</i> lipoglycans conveyed by BVs that are produced by <i>M. tuberculosis</i> and released from infected macrophages. These lipoglycans are transferred to T cells to inhibit T cell responses, providing a mechanism that may promote immune evasion.