Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, Illinois, United States of America.
PLoS Pathog. 2010 Feb 26;6(2):e1000789. doi: 10.1371/journal.ppat.1000789.
Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB) granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vgamma2Vdelta2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNgamma-producing Vgamma2Vdelta2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNgamma neutralizing Ab treatment reversed the HMBPP-mediated down-regulation effect on IL-22-producing T cells, suggesting that Vgamma2Vdelta2 T-cell-driven IFNgamma-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vgamma2Vdelta2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB.
人类 IL-22 产生 T 细胞在感染中的分化、分布和免疫调节仍不清楚。在这里，我们在非人类灵长类动物模型中证明，结核分枝杆菌感染导致能够在没有体外抗原刺激的情况下新产生 IL-22 的 T 细胞数量明显增加，并更显著地将这些细胞分布在肺部，而不是血液和淋巴组织中。一致地，通过共聚焦显微镜和免疫组织化学在肺结核（TB）肉芽肿中在原位可视化了产生 IL-22 的 T 细胞，表明成熟的产生 IL-22 的 T 细胞存在于 TB 肉芽肿中。令人惊讶的是，磷酸抗原 HMBPP 激活 Vγ2Vδ2 T 细胞下调了血液、肺/BAL 液、脾和淋巴结淋巴细胞中新产生 IL-22 的 T 细胞的能力。HMBPP 刺激后 IFNγ 产生的 Vγ2Vδ2 T 效应细胞的上调与这些 T 细胞新产生 IL-22 的能力下调同时发生。重要的是，抗 IFNγ 中和 Ab 处理逆转了 HMBPP 介导的对产生 IL-22 的 T 细胞的下调作用，表明 Vγ2Vδ2 T 细胞驱动的 IFNγ 网络功能是 HMBPP 介导的下调 T 细胞产生 IL-22 的能力的机制。这些新发现提出了最终研究产生 IL-22 的 T 细胞功能的可能性，并为靶向 Vγ2Vδ2 T 细胞以平衡严重 TB 中潜在过度激活的产生 IL-22 的 T 细胞提供了可能性。
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