Enhancing antigen-based therapy for T1D by T cell coreceptor tuning

摘要/摘要 目前，1型糖尿病(T1D)还没有治愈方法。由于免疫调节对胰岛素的破坏- 在生产细胞的过程中，T1D的治疗仅限于每日外源性胰岛素注射。需要的是 长期有效抑制细胞自身免疫以预防和治疗T1D的免疫疗法。一 方法是应用细胞自身抗原诱导适应性调节性T细胞分化 单元(ATREG)。这种方法很有吸引力，因为在保留获得性免疫的同时，可以选择性地针对自身免疫 豁免权不受干扰。然而，一个主要的障碍是诱导一个足够大的和子集多样化的ATREG池， 同时避免致病效应T细胞(TEF)的扩张。ATREG池的大小和性质是 在临床前T1D晚期和临床糖尿病发作时尤其重要，当高频率 糖尿病致病的CD_4~+和CD_8~+T细胞因子。这本R21概述了一种新的方法来增强 通过调节CD4的功能来进行抗原治疗。与MHCII结合的CD4激活一个信号级联， 有助于增强整体TCR信令强度。我们假设调节CD4功能和TCR信号 强度，导致通过抗原疫苗增加和选择性地诱导ATREG。在我们的模型中， ATREG亚群的分化是通过改变辅受体调节(COT)的水平来决定的。我们将聘用 不耗竭的抗体实现COT。此R21的主要目标是初步了解 COT选择性促进ATREG分化的机制(目标1)，并确定治疗 这一组合办法的有效性(目标2)。如果成功，COT和自身抗原联合接种是 有望不仅适用于T1D的预防和治疗，还可用于其他T细胞介导的 自身免疫性疾病和病理学。

SUMMARY/ABSTRACT Currently no cure exists for Type 1 diabetes (T1D). Due to immune-mediated destruction of the insulin- producing  cells, treatment of T1D is limited to daily exogenous insulin administration. Needed are immunotherapies that effectively suppress  cell autoimmunity longterm in order to prevent and treat T1D. One approach is the administration of cell autoantigens to induce differentiation of adaptive regulatory CD4+ T cells (aTreg). The approach is appealing since autoimmunity can be selectively targeted while leaving acquired immunity unperturbed. A major hurdle, however, is inducing a sufficiently sized and subset diverse aTreg pool, while avoiding expansion of pathogenic effector T cells (Teff). The size and nature of the aTreg pool is particularly important at late preclinical T1D stages and at the onset of clinical diabetes, when a high frequency of diabetogenic CD4+ and CD8+ Teff is found. This R21 outlines a novel approach to enhance the efficacy of antigen therapy by “tuning” the function of CD4. CD4 binding to MHCII activates a signaling cascade that contributes to overall TCR signaling strength. We hypothesize that modulating CD4 function and TCR signaling strength, results in increased and selective induction of aTreg by antigen vaccination. In our model, differentiation of aTreg subsets is determined by varying the level of coreceptor tuning (CoT). We will employ nondepleting CD4 antibody to achieve CoT. Key objectives of this R21 are to gain initial insight into the mechanism(s) by which CoT selectively promotes aTreg differentiation (Aim 1), and determine the therapeutic efficacy of this combinatorial approach (Aim 2). If successful, combined CoT and self-antigen vaccination is expected to be applicable not only for the prevention and treatment of T1D, but also for other T cell-mediated autoimmune diseases and pathologies.