Immune Regualtion and Type 1 Diabetes Pathogenesis

我们和其他人最近调查了1型糖尿病患者的频率和功能， 调节性T细胞（Treg）群体，其特征在于同时表达CD 4和CD 25。我们 研究并不支持改变的CD 4 + CD 25 + T细胞频率与1型糖尿病相关的观点。 糖尿病，而是确定了1型糖尿病相关的改变，这些细胞的功能活动， 在体外抑制效应T（Teff）细胞应答的术语。需要解决的问题 上述已发表的1型糖尿病中Treg频率和功能的差异，以及 调查Teff细胞缺陷的可能性，将提供扩大的研究，包括 年龄，代谢控制和疾病持续时间的参数，以及定义（与项目 1和2）这种缺陷背后的细胞和分子机制。因此， 项目三是进一步了解CD 4 + CD 25 + T细胞的免疫调节机制。 细胞，确定其对1型糖尿病发病机制的贡献，并评估这些细胞的潜力。 细胞作为自身免疫性疾病活动的标志物。我们的具体目标是测试 假设Treg细胞在1型糖尿病中是功能缺陷的，由于调节异常， 与APC，Teff和NKT细胞的相互作用，并且这种缺陷的细胞和分子基础存在于 这些信号通路控制Treg的表型特征，包括表面CD 25、FOXP 3以及TGF β 5。 这一假设是基于我们对人乳腺癌中Treg功能活性缺陷的观察而形成的。 人类1型糖尿病，最近的数据表明，CD 25的表面表达/稳定性对 维持Treg和Teff之间的调节稳态，文献表明免疫突触 与其他免疫系统细胞（例如，DC、NKT细胞）也可能影响Treg的功能活性 作为提示有限数量的细胞因子的关键作用的信息（例如，IL-2、IL-10、TGF β）和基质 金属蛋白酶与这些调节过程有关。该项目有两个具体目标：1） 确定年龄、1型糖尿病和代谢控制对糖尿病的频率和功能的影响。 通过CD 4和CD 25的共表达定义的调节性T细胞，以及对 叉头转录因子FoxPS。2)定义以下缺陷的分子机制： 1型糖尿病患者的CD 4 + CD 25 + T细胞功能这些研究的成功完成 可以提供关键信息，以填补现有的知识空白，关于机械的相互作用， 在特定的细胞群之间，这些细胞群是导致1型糖尿病的免疫调节失败的基础。 糖尿病

We and others have recently investigated patients with type 1 diabetes for the frequency and function of a population of regulatory T cells (Treg), characterized by the simultaneous expression of CD4 and CD25. Our studies did not support the notion that altered CD4+CD25+ T cell frequencies are associated with type 1 diabetes, but rather identified type 1 diabetes related alterations in the functional activities of these cells in terms of suppressing effector T (Teff) cell responses in vitro. The need to bring resolution to the aforementioned published discrepancies in frequency and function of Treg in type 1 diabetes, as well as investigate the potential for Teff cell defects, would be afforded with expanded studies that include the parameters of age, metabolic control, and disease duration, as well as to define (in association with Projects 1 and 2) the cellular and molecular mechanism(s) underlying this defect. Therefore, the overall objective of Project 3 is to improve our understanding the mechanisms of immune regulation afforded by CD4+CD25+ T cells, identify their contribution to the pathogenesis of type 1 diabetes, and evaluate the potential of these cells to serve as a marker for autoimmune disease activity. Our specific aims are designed to test the hypothesis that Treg cells are functionally defective in type 1 diabetes, as a result of dysregulated interactions with APC, Teff, and NKT cells, and that the cellular & molecular basis for this defect resides in pathways controlling the phenotypic signature of Treg including surface CD25, FOXP3, as well as TGFfS. This hypothesis has been formed based on our observations of deficient functional activities of Treg in human type 1 diabetes, recent data suggesting the surface expression/stability of CD25 is crucial to maintaining regulatory homeostasis between Treg and Teff, literature indicating the immunological synapse with other immune system cells (e.g., DC, NKT cells) may influence the functional activities of Treg, as well as information suggesting key roles for a limited number of cytokines (e.g., IL-2, IL-10, TGFp) and matrix metalloproteinases are associated with these regulatory processes. The Project has two specific aims: 1) Identify the influence of age, type 1 diabetes, and metabolic control on the frequency and function of regulatory T cells defined by co-expression of CD4 and CD25, as well as on the cellular expression of the fork-head transcription factor FoxPS. 2) Define the molecular mechanisms underlying deficiencies in CD4+CD25+ T cell function in subjects with type 1 diabetes. The successful completion of these studies could provide key information to fill an existing knowledge void regarding the mechanistic interactions between specific cell populations that underlie the failure of immune regulation which results in type 1 diabetes.