The CD226 and TIGIT Costimulatory Axis in Type 1 Diabetes

 描述(申请人提供)：1型糖尿病(T1D)的发展依赖于传递疾病易感性的基因和环境因素之间的复杂相互作用。这些相互作用影响免疫系统的细胞，这些细胞介导产生胰岛素的胰腺细胞的自身免疫破坏。尽管已有近40个基因被确定为T1D的遗传风险，但这些特定基因变异对功能的影响仍然缺乏特征。我们的研究旨在通过了解CD226(一种与多种自身免疫性疾病的风险相关的基因)影响免疫调节并可能在高危人群中引发自身免疫性疾病的机制来解决这一知识鸿沟。CD226是一种免疫共刺激分子，与具有Ig和ITIM结构域的抑制性T细胞免疫受体(TIGIT)竞争结合抗原提呈细胞(APC)上表达的CD155或CD112。CD226：TIGIT调节轴在许多方面与CD28和CTLA-4相互作用相似，CD28和CTLA-4相互作用已导致有效的免疫调节疗法用于癌症、移植和自身免疫的治疗。我们的初步数据表明，T细胞上CD226的表达与分化记忆和效应器T细胞亚群密切相关，这些亚群被广泛认为是导致细胞破坏的原因。此外，CD226表达在调节性T细胞(Treg)的一个独特亚群上，表现出表观遗传不稳定性，抑制能力降低，并产生细胞因子。这些数据导致了我们的假设，即疾病相关变体和炎症环境触发因素导致CD226功能失衡：TIGIT调节轴支持CD226激活免疫，而不是T1D中TIGIT的调节。我们将通过实施一系列目标来验证这一假说：i)确定调节CD226和TIGIT表达对T细胞激活和调节的影响，ii)评估CD226和TIGIT在T1D自然病程中在非肥胖糖尿病小鼠模型和患有T1D的人类中的表达，以及iii)测试靶向这一轴的治疗潜力，以产生用于过继免疫治疗的稳定调节T细胞。这些研究将使用新的工具，包括慢病毒表达系统，动物模型和人类T细胞的定向基因靶向，以及利用独特的临床资源来解决患有T1D的人类自身免疫攻击部位的这个问题。总之，来自这些目标的数据有望提供关于影响自身免疫性疾病发展的关键免疫检查点的信息，并最终导致阻止T1D中细胞的自身免疫破坏的新的治疗干预措施。

 DESCRIPTION (provided by applicant): The development of Type 1 Diabetes (T1D) relies on complex interactions between genes imparting disease susceptibility and environmental factors. These interactions influence the cells of the immune system that mediate the autoimmune destruction of insulin-producing pancreatic  cells. Despite the nearly 40 genes that have been identified to confer genetic risk for T1D, the functional impact of these specific gene variants remain poorly characterized. Our studies are designed to address this knowledge gap by providing an understanding for the mechanism by which CD226, a gene linked to risk for multiple autoimmune disorders, impacts immune regulation and may precipitate autoimmune disease in those at risk. CD226 is an immune costimulatory molecule that competes with an inhibitory receptor known as T-cell immunoreceptor with Ig and ITIM domain (TIGIT) for binding to CD155 or CD112 expressed on antigen presenting cells (APC). The CD226:TIGIT regulatory axis is analogous in many ways to the well characterized CD28 and CTLA-4 interaction that has resulted in potent immune modulating therapeutics for the treatment of cancer, transplantation, and autoimmunity. Our preliminary data suggest that CD226 expression on T cells is tightly linked to differentiated memory and effector T cell subsets that are widely thought to drive  cel destruction. In addition, CD226 is expressed on a unique subset of regulatory T cells (Tregs) that exhibit epigenetic instability, reduced suppressive capacity, and produce cytokines. These data have led us to propose the hypothesis that disease-associated variants and inflammatory environmental triggers result in a functional imbalance in the CD226:TIGIT regulatory axis favoring immune activation by CD226 over regulation by TIGIT in T1D. We will test this hypothesis by conducting a series of Aims to i) determine the impact of modulating CD226 and TIGIT expression on T cell activation and regulation, ii) assessing the expression of CD226 and TIGIT throughout the natural history of T1D in the Non-Obese Diabetic mouse model and in humans with T1D, and iii) testing the therapeutic potential of targeting this axis to generate stable regulatory T cells for adoptive immune therapy. These studies will employ novel tools including lentiviral expression systems, directed gene targeting of animals models and human T cells, and the utilization of unique clinical resources to address this question at the site of autoimmune attack in humans with T1D. In sum, data from these Aims are expected to provide information about a key immune checkpoint that impacts autoimmune disease development, and ultimately, lead to novel therapeutic interventions to halt the autoimmune destruction of  cells in T1D.