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

描述（由申请人提供）：1型糖尿病是一种自身免疫性疾病，可能由于未能对胰腺中存在的自身抗原产生免疫耐受而引起。在NOD小鼠中，由于中枢耐受性的胸腺缺陷而发展为1型糖尿病，产生α/β T细胞，其攻击胰腺并使其不能产生胰岛素。诱导对关键自身抗原的外周免疫耐受的各种方法可以延迟或降低1型糖尿病的严重程度。人类和NOD小鼠糖尿病中的主要自身抗原是胰岛素，我们最近发现γ/δ T细胞对许多致糖尿病α/β T细胞识别的相同胰岛素肽做出反应，所述胰岛素肽在NOD胰腺中天然产生。由于对糖尿病患者的研究表明，γ/δ T细胞可能是疾病发展的重要因素，并且由于三项不同的NOD背景小鼠研究现已表明γ/δ 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γ/δ T细胞如何影响这种疾病提供了令人信服的论据。我们现在已经产生了不能产生γ/δ T细胞的NOD小鼠，NOD. TCR δ-/-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γ/δ T细胞代表了一个不同的子集，它改变了自身攻击性α/β T细胞的反应。首先，我们将测试NOD. TCR δ-/-小鼠，以确定γ/δ T细胞实际上是否可以减缓或降低自发NOD模型中1型糖尿病的严重程度。其次，由于不同的γ/δ T细胞亚群通常具有不同的功能，我们将使用NOD/SCID过继转移模型来确定是否所有γ/δ T细胞或仅某一类型的γ/δ T细胞可以预防糖尿病。我们还将研究由相关γ/δ T细胞产生的某些细胞因子候选物的作用，以阐明这种保护是如何介导的。 公共卫生相关性：一些出版物表明，一种相对罕见的T细胞类型，称为γ/δ T细胞，在决定是否发生1型糖尿病方面很重要。这些细胞在一些实验模型中显示在1型糖尿病中起抑制作用，但尚不清楚它们是否也能够在疾病的正常发展过程中发挥作用。本研究的目的是确定这些γ/δ T细胞是否影响自发发展的小鼠1型糖尿病的发病率或疾病的严重程度，并确定抑制性γ/δ T细胞的特征。这项工作可能会导致通过刺激抑制性γ/δ T细胞来减缓或预防1型糖尿病的新方法。

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. PUBLIC HEALTH RELEVANCE: Several publications have suggested that a relatively rare T cell type, known as the gamma/delta T cell, is important in determining whether or not type 1diabetes develops. These cells were shown in some experimental models to play a suppressive role in type 1 diabetes, but it is not yet clear whether they are also able do so during normal development of the disease. The purpose of this study is to determine whether these gamma/delta T cells affect the incidence or severity of disease in spontaneously developing mouse type 1diabetes, and to determine the characteristics of the suppressive gamma/delta T cells. This work could lead to new methods of slowing or preventing type 1 diabetes, via the stimulation of suppressive gamma/delta T cells.