The role of gamma/delta T cells in type 1 diabetes

描述(申请人提供)：1型糖尿病是一种自身免疫性疾病，可能是由于未能对胰腺中存在的自身抗原产生免疫耐受而引起的。在NOD小鼠中，由于胸腺中枢耐受缺陷而患上1型糖尿病，产生的α/βT细胞攻击胰腺，使其无法产生胰岛素。各种诱导外周免疫耐受关键自身抗原的方法可以延缓或减轻1型糖尿病的严重程度。人类和NOD小鼠糖尿病中的一个主要自身抗原是胰岛素，我们最近发现，伽马/德尔塔T细胞对许多糖尿病原发的α/βT细胞识别的胰岛素肽做出反应，这种胰岛素肽是在NOD胰腺自然产生的。由于对糖尿病患者的研究表明，伽马/德尔塔T细胞可能是疾病发展的一个重要因素，而且三项针对NOD背景小鼠的不同研究现已表明，伽马/德尔塔T细胞可以抑制1型糖尿病的发展，这些发现共同为进一步研究伽马/德尔塔T细胞如何影响这种疾病提供了令人信服的论据。我们现在已经培育出不能产生伽马/德尔塔T细胞的NOD小鼠，在这个项目中，我们将使用这些小鼠来测试这样一个假设，即预防或减少1型糖尿病的伽马/德尔塔T细胞代表着改变自身侵袭性α/βT细胞反应的一个独特的亚群。首先，我们将测试NOD.TCRDelta-/-小鼠，以确定在自发的NOD模型中，Gamma/Delta T细胞是否确实可以减缓或减轻1型糖尿病的严重程度。其次，由于不同的伽马/德尔塔T细胞亚群通常具有不同的功能，我们将使用NOD/SCID采用转移模型来确定是否所有的伽玛/德尔塔T细胞，或者只有一种类型，可以预防糖尿病。我们还将研究由相关的伽马/德尔塔T细胞产生的某些候选细胞因子的作用，以阐明这种保护是如何介导的。

DESCRIPTION (provided by applicant): Type 1 diabetes is an autoimmune disease that can arise due to a failure to develop immunological tolerance to self-antigens present in the pancreas. In NOD mice, which develop type 1 diabetes due to a thymic defect in central tolerance, alpha/beta T cells are produced that attack the pancreas and render it unable to produce insulin. Various methods of inducing peripheral immune tolerance to critical self-antigens can delay or decrease the severity of type 1 diabetes. A major self-antigen in both human and NOD mouse diabetes is insulin, and we recently discovered that gamma/delta T cells respond to the same insulin peptide that is recognized by many diabetogenic alpha/beta T cells, which is generated naturally in the NOD pancreas. Because studies on diabetes patients suggested that gamma/delta T cells may be an important factor in the development of the disease, and because three different studies with NOD background mice have now shown that gamma/delta T cells can suppress the development of type 1 diabetes, these findings together make a compelling argument for the further study of how gamma/delta T cells affect this disease. We have now generated NOD mice incapable of producing gamma/delta T cells, NOD.TCRdelta-/- mice, and in this project will use these mice to test the hypothesis that gamma/delta T cells which prevent or reduce type 1 diabetes represent a distinct subset that alters the response of autoaggressive alpha/beta T cells. First, we will test NOD.TCRdelta-/- mice to ascertain whether gamma/delta T cells in fact can slow or reduce the severity of type 1 diabetes in the spontaneous NOD model. Second, because different gamma/delta T cell subsets often have distinct functions, we will determine whether all gamma/delta T cells, or only a certain type, can protect against diabetes, using a NOD/SCID adoptive transfer model. We will also investigate the role of certain cytokine candidates produced by the relevant gamma/delta T cells, towards elucidating how this protection is mediated.