Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
Department of Psychiatry, Western University, London, Ontario, Canada.
Brain Behav Immun. 2019 Aug;80:793-804. doi: 10.1016/j.bbi.2019.05.027. Epub 2019 May 17.
Stress is known to impede certain host defense mechanisms, including those governed by conventional T lymphocytes. However, whether innate-like T lymphocytes, such as invariant natural killer T (iNKT) and mucosa-associated invariant T (MAIT) cells, are impacted by stress is unclear. Herein, we report that prolonged psychological stress caused by physical confinement results in robust upregulation of T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), an immune checkpoint receptor that controls antitumor and antiviral immune responses. Elevated TIGIT expression was found not only on NK and conventional T cells, but also on iNKT and MAIT cells. Stress-provoked TIGIT upregulation was reversed through treatment with the glucocorticoid receptor (GR) antagonist RU486, but not with 6-hydroxydopamine that induces chemical sympathectomy. A Cre/Lox gene targeting model in which GR was ablated in cells expressing Lck under its proximal promoter revealed that TIGIT upregulation in stressed animals stems from direct GR signaling in T and iNKT cells. In fact, long-term oral administration of exogenous corticosterone (CS) to wild-type C57BL/6 (B6) mice was sufficient to increase TIGIT expression levels on T and iNKT cells. In vitro treatment with CS also potently and selectively upregulated TIGIT, but not CTLA-4 or LAG-3, on mouse iNKT and MAIT hybridomas. These results were recapitulated using primary hepatic iNKT and MAIT cells from wild-type B6 and B6.MAIT mice, respectively. Subjecting B6.MAIT mice to physical restraint also raised the frequency of TIGIT cells among hepatic MAIT cells in a GR-dependent manner. Finally, we found that TIGIT is similarly upregulated in a chronic variable stress model in which animals are exposed to unpredictable heterotypic stressors without developing habituation. Taken together, our findings link, for the first time to our knowledge, GR signaling to TIGIT expression. We propose that glucocorticoid hormones dampen immune responses, in part, by enhancing TIGIT expression across multiple critical subsets of effector lymphocytes, including innate-like T cells. Therefore, TIGIT may constitute an attractive target in immune-enhancing interventions for sustained physiological stress.
压力已知会阻碍某些宿主防御机制，包括传统 T 淋巴细胞所调控的机制。然而，压力是否会影响先天样 T 淋巴细胞，如不变自然杀伤 T（iNKT）和黏膜相关不变 T（MAIT）细胞，尚不清楚。在此，我们报告称，由身体限制引起的长期心理压力导致 T 细胞免疫受体与免疫球蛋白和 ITIM 结构域（TIGIT）的强烈上调，TIGIT 是一种控制抗肿瘤和抗病毒免疫反应的免疫检查点受体。不仅在 NK 和传统 T 细胞上，而且在 iNKT 和 MAIT 细胞上都发现了升高的 TIGIT 表达。应激引起的 TIGIT 上调可通过糖皮质激素受体（GR）拮抗剂 RU486 逆转，但不能通过诱导化学交感神经切除术的 6-羟多巴胺逆转。在细胞中表达 Lck 下的近端启动子时，GR 被剔除的 Cre/Lox 基因靶向模型表明，应激动物中 TIGIT 的上调源自 T 和 iNKT 细胞中的直接 GR 信号。事实上，长期口服外源性皮质酮（CS）足以增加野生型 C57BL/6（B6）小鼠 T 和 iNKT 细胞上的 TIGIT 表达水平。CS 的体外处理也强有力且选择性地上调了 TIGIT，但不上调 CTLA-4 或 LAG-3，在小鼠 iNKT 和 MAIT 杂交瘤上。这些结果分别使用来自野生型 B6 和 B6.MAIT 小鼠的原发性肝 iNKT 和 MAIT 细胞进行了再现。通过身体限制使 B6.MAIT 小鼠应激也以 GR 依赖性方式增加了肝 MAIT 细胞中 TIGIT 细胞的频率。最后，我们发现，在一种慢性可变应激模型中，当动物暴露于不可预测的异型应激源而不产生习惯化时，TIGIT 也会类似地上调。综上所述，我们的研究结果首次将 GR 信号与 TIGIT 表达联系起来。我们提出，糖皮质激素通过增强多种关键效应淋巴细胞亚群，包括先天样 T 细胞的 TIGIT 表达，来抑制免疫反应。因此，TIGIT 可能成为持续生理应激免疫增强干预的有吸引力的靶点。
