Lucca Liliana E, Axisa Pierre-Paul, Singer Emily R, Nolan Neal M, Dominguez-Villar Margarita, Hafler David A
Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
JCI Insight. 2019 Feb 7;4(3):e124427. doi: 10.1172/jci.insight.124427.
Th1 Tregs are characterized by the acquisition of proinflammatory cytokine secretion and reduced suppressor activity. Th1 Tregs are found at increased frequency in autoimmune diseases, including type 1 diabetes and multiple sclerosis (MS). We have previously reported that in vitro stimulation with IL-12 recapitulates the functional and molecular features of MS-associated Th1 Tregs, revealing a central role for hyperactivation of the Akt pathway in their induction. TIGIT is a newly identified coinhibitory receptor that marks Tregs that specifically control Th1 and Th17 responses. Here, we report that signaling through TIGIT counteracts the action of IL-12 in inducing the Th1 program. Specifically, TIGIT signaling represses production of IFN-γ and T-bet expression and restores suppressor function in Tregs treated with IL-12. FoxO1 functional inhibition abolishes the protective effect of TIGIT, indicating that TIGIT signaling promotes FoxO1 nuclear localization. Consistent with this observation, signaling through TIGIT leads to a rapid suppression of Akt function and FoxO1 phosphorylation. Finally, TIGIT stimulation reduces the production of IFN-γ and corrects the suppressor defect of Tregs from patients with MS. Our results indicate an important role for TIGIT in controlling the functional stability of Tregs through repression of Akt, suggesting that the TIGIT pathway could be targeted for immunomodulatory therapies in human autoimmune disorders.
Th1调节性T细胞的特征是获得促炎细胞因子分泌能力且抑制活性降低。在包括1型糖尿病和多发性硬化症（MS）在内的自身免疫性疾病中，Th1调节性T细胞的频率增加。我们之前报道过，用白细胞介素-12进行体外刺激可重现与MS相关的Th1调节性T细胞的功能和分子特征，揭示了Akt途径的过度激活在其诱导过程中的核心作用。TIGIT是一种新发现的共抑制受体，可标记特异性控制Th1和Th17反应的调节性T细胞。在此，我们报道通过TIGIT发出的信号可抵消白细胞介素-12在诱导Th1程序中的作用。具体而言，TIGIT信号传导可抑制干扰素-γ的产生和T-bet表达，并恢复用白细胞介素-12处理的调节性T细胞的抑制功能。FoxO1功能抑制可消除TIGIT的保护作用，表明TIGIT信号传导促进FoxO1核定位。与这一观察结果一致，通过TIGIT发出的信号会导致Akt功能和FoxO1磷酸化迅速受到抑制。最后，TIGIT刺激可减少干扰素-γ的产生，并纠正MS患者调节性T细胞的抑制缺陷。我们的结果表明，TIGIT在通过抑制Akt来控制调节性T细胞的功能稳定性方面具有重要作用，这表明TIGIT途径可作为人类自身免疫性疾病免疫调节治疗的靶点。
