Analyzing and modulating immunoregulatory defects in autoimmune disease.

天然存在的CD 4 + CD 25+调节性T细胞在控制自身免疫中是重要的。 虽然胸腺似乎是CD 4 + CD 25 + T细胞发育的主要部位，但它仍然是CD 4 + CD 25 + T细胞发育的主要部位。 不清楚周边是否也有开发地点。我们最近发现， CD 4 + CD 25 + T细胞在体内可转化为CD 4 + CD 25+调节性T细胞。 外围CD 4 + CD 25 + T细胞向CD 4 + CD 25+调节性T细胞的转化可能是一个非常重要的过程。 外周CD 4 + CD 25+调节性T细胞稳态和维持重要机制， 这个过程中的缺陷可能会导致自身免疫性疾病的发展。我们有 发现糖尿病前期NOD小鼠的CD 4 + CD 25 + T细胞百分比正常， 胸腺，但在外周的百分比显着较低。此外，NOD CD 4 + CD 25-T 细胞不能在体内转化为具有调节功能的CD 4 + CD 25+细胞， 这表明NOD小鼠可能在这一转换过程中存在缺陷，因此， 无法维持这一监管人口。这一提议的核心假设是， NOD小鼠中CD 4 + CD 25 + T细胞向CD 4 + CD 25+调节性T细胞的转化增强 可以预防糖尿病。我们将通过研究 NOD小鼠的转化，确定这一过程是否可以恢复， 与疾病的改善有关。通过对转化缺陷的认识， 在NOD小鼠中，CD 4 + CD 25 + T细胞转化为CD 4 + CD 25+调节性T细胞， 制定策略来克服这些缺陷，从而开发治疗方法来预防或治疗 自身免疫性疾病

Naturally occurring CD4+CD25+ regulatory T cells are important in controlling autoimrnunity. Although the thymus appears to be a major site of CD4+CD25+ T cell development, it is still unclear whether there are also peripheral sites of development. We have found recently that CD4+CD25~ T cells can be converted into CD4+CD25+ regulatory T cells in vivo in the periphery. Conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells may be a very important mechanism for peripheral CD4+CD25+ regulatory T cell homeostasis and maintenance, and a defect in this process could contribute to autoimmune disease development. We have found that prediabetic NOD mice have a normal percentage of CD4+CD25+ T cells in the thymus, but a significantly lower percentage in the periphery. Furthermore, NOD CD4+CD25"T cells are unable to convert in vivo into CD4+CD25+ cells that have regulatory function, strongly suggesting that NOD mice may have a defect in this conversion process and may, therefore, be unable to maintain this regulatory population. The central hypothesis of this proposal is that enhanced conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice can prevent diabetes. We will test this hypothesis by studying the mechanisms and defects in conversion in NOD mice, determinewhether this process can be restored and whether restoration is associated with amelioration of disease. By understanding the defects in conversion of CD4+CD25" T cells into CD4+CD25+ regulatory T cells in NOD mice, it may be possible to devise strategies to overcome these defects and,thereby, develop therapies to prevent or treat autoimmune disease.