Immune homeostasis enforced by co-localized effector and regulatory T cells.
Immune homeostasis enforced by co-localized effector and regulatory T cells.
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DOI：
10.1038/nature16169
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发表时间：
2015-12-10
期刊：
影响因子：
64.8
通讯作者：
Germain RN
中科院分区：
文献类型：
--
作者：
Liu Z;Gerner MY;Van Panhuys N;Levine AG;Rudensky AY;Germain RN
Foxp3+ 调节性 T 细胞 (Treg) 通过限制逃避胸腺阴性选择或细胞自主外周失活的常规 T 细胞的效应活性，在预防自身免疫性疾病中发挥关键作用。然而，尽管有大量关于介导 Treg 功能干扰自身攻击性效应反应的分子参与者的信息，但完整组织中的相关细胞事件在很大程度上仍未得到探索，而且 Tregs 是否阻止自身特异性 T 细胞的激活或主要发挥限制此类细胞损伤的作用的问题尚未得到解决。在这里，我们采用多重、高分辨率、定量成像来揭示，在大多数次级淋巴组织中，表达磷酸化 STAT5 (pSTAT5) 的 Tregs 和大量抑制分子 CD73 和 CTLA-4 存在于离散的簇中，其中罕见的 IL-2 产生效应 T 细胞被自身抗原激活。这种局部 IL-2 的产生会诱导 Tregs 中的 STAT5 磷酸化，并且是反馈回路的一部分，可增强 Tregs 的抑制特性，从而限制进一步的自身免疫反应。 Tregs 对 TCR 表达的诱导性消融降低了它们的调节能力并破坏了它们在此类簇中的定位，导致效应 T 细胞反应不受控制。因此，我们的数据表明，自身反应性 T 细胞定期达到激活和细胞因子基因诱导的状态，物理上共聚集、TCR 刺激的 Tregs 以反馈方式响应这种激活，以抑制初期自身免疫并维持免疫稳态。
Foxp3+ regulatory T cells (Tregs) play a critical role in preventing autoimmune disease by limiting the effector activity of conventional T cells that have escaped thymic negative selection or cell-autonomous peripheral inactivation. However, despite the substantial information available about the molecular players mediating Treg functional interference with auto-aggressive effector responses, the relevant cellular events in intact tissues remain largely unexplored and the issues of whether Tregs prevent activation of self-specific T cells or function primarily to limit damage from such cells have not been addressed. Here we have employed multiplex, high-resolution, quantitative imaging to reveal that within most secondary lymphoid tissues, Tregs expressing phosphorylated STAT5 (pSTAT5) and high amounts of the suppressive molecules CD73 and CTLA-4 exist in discrete clusters with rare IL-2 producing effector T cells activated by self-antigens. This local IL-2 production induces the STAT5 phosphorylation in the Tregs and is part of a feedback circuit that augments the suppressive properties of the Tregs to limit further autoimmune responses. Inducible ablation of TCR expression by Tregs reduces their regulatory capacity and disrupts their localization in such clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells reach a state of activation and cytokine gene induction on a regular basis, with physically co-clustering, TCR-stimulated Tregs responding to this activation in a feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.