Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation.
Mycobacterium tuberculosis Membrane Vesicles Inhibit T Cell Activation.
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DOI：
10.4049/jimmunol.1601199
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Harding CV
中科院分区：
文献类型：
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作者：
Athman JJ;Sande OJ;Groft SG;Reba SM;Nagy N;Wearsch PA;Richardson ET;Rojas R;Boom WH;Shukla S;Harding CV
结核分枝杆菌利用多种机制逃避宿主免疫应答，并通过M.结核病可能有助于免疫逃避。T细胞受体信号传导被M.结核菌细胞外膜脂多糖，如脂阿拉伯甘露聚糖和脂甘露聚糖，但脂多糖从M.结核病感染的巨噬细胞内到达T细胞是未知的。在这些研究中，我们发现M.结核病和从感染的巨噬细胞释放抑制CD 4 + T细胞的活化，如白细胞介素-2的产生减少和T细胞增殖减少所示。流式细胞术和western blot检测表明，M.结核病衍生的细菌囊泡（BV）被转移到T细胞，在那里它们抑制T细胞应答。在BV存在下刺激CD 4 + T细胞诱导GRAIL的表达，GRAIL是T细胞无反应性的标志物;在再刺激后，这些T细胞显示出增殖能力降低，证实了T细胞无反应性的状态。此外，脂阿拉伯甘露聚糖与T细胞在体外与感染的巨噬细胞孵育后以及从M.结核病感染的小鼠，证实了脂阿拉伯甘露聚糖在体内向T细胞运输的发生。这些研究证明了一种新的机制，直接调节CD 4 + T细胞的M。由M.结核病和释放从感染的巨噬细胞。这些脂聚糖被转移到T细胞以抑制T细胞应答，提供了可能促进免疫逃避的机制。
Mycobacterium tuberculosis utilizes multiple mechanisms to evade host immune responses, and inhibition of effector CD4+ T cell responses by M. tuberculosis may contribute to immune evasion. T cell receptor signaling is inhibited by M. tuberculosis cell envelope lipoglycans, such as lipoarabinomannan and lipomannan, but a mechanism for lipoglycans to traffic from M. tuberculosis within infected macrophages to reach T cells is unknown. In these studies, we found that membrane vesicles produced by M. tuberculosis and released from infected macrophages inhibited the activation of CD4+ T cells, as indicated by reduced production of interleukin-2 and reduced T cell proliferation. Flow cytometry and western blot demonstrated that lipoglycans from M. tuberculosis-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 M. tuberculosis-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 M. tuberculosis lipoglycans conveyed by BVs that are produced by M. tuberculosis 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.