Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 2011 Feb 1;186(3):1338-42. doi: 10.4049/jimmunol.1003081. Epub 2011 Jan 3.
Costimulatory molecules regulate the functional outcome of T cell activation, and disturbance of the balance between activating and inhibitory signals results in increased susceptibility to infection or the induction of autoimmunity. Similar to the well-characterized CD28/CTLA-4 costimulatory pathway, a newly emerging pathway consisting of CD226 and T cell Ig and ITIM domain (TIGIT) has been associated with susceptibility to multiple autoimmune diseases. In this study, we examined the role of the putative coinhibitory molecule TIGIT and show that loss of TIGIT in mice results in hyperproliferative T cell responses and increased susceptibility to autoimmunity. TIGIT is thought to indirectly inhibit T cell responses by the induction of tolerogenic dendritic cells. By generating an agonistic anti-TIGIT Ab, we demonstrate that TIGIT can inhibit T cell responses directly independent of APCs. Microarray analysis of T cells stimulated with agonistic anti-TIGIT Ab revealed that TIGIT can act directly on T cells by attenuating TCR-driven activation signals.
共刺激分子调节 T 细胞激活的功能结果，激活和抑制信号之间平衡的破坏导致易感性增加感染或自身免疫的诱导。类似于特征明确的 CD28/CTLA-4 共刺激途径，由 CD226 和 T 细胞免疫球蛋白和 ITIM 结构域（TIGIT）组成的新出现的途径与多种自身免疫性疾病的易感性相关。在这项研究中，我们研究了假定的共抑制分子 TIGIT 的作用，并表明小鼠中 TIGIT 的缺失导致 T 细胞过度增殖反应和自身免疫易感性增加。TIGIT 被认为通过诱导耐受树突状细胞间接抑制 T 细胞反应。通过产生激动性抗 TIGIT Ab，我们证明 TIGIT 可以直接抑制 T 细胞反应而不依赖于 APC。用激动性抗 TIGIT Ab 刺激的 T 细胞的微阵列分析表明，TIGIT 可以通过减弱 TCR 驱动的激活信号直接作用于 T 细胞。
