Sex-based differences in regulatory T cell responses

描述(申请人提供)：许多自身免疫性疾病 女性比男性更常见，包括多发性硬化症、关节炎 和系统性红斑狼疮。尽管造成这种差异的原因是 性激素目前还不为人所知，但可能会发挥重要作用。一个 自然产生的调节性T细胞群，CD4+CD25+调节性T细胞 细胞，最近被描述为负责控制 小鼠的自身免疫性疾病。在小鼠中消除这一群体导致 严重的多器官自身免疫性疾病。已经发现了一个同源群体 在人类身上，似乎表达了类似的功能特性，至少在 体外试验。我们的初步结果表明，无论是定量的还是 艾滋病患者外周血中CD4+CD25+调节性T细胞数量存在质的差异 成年，但不是青春期前，雌性与雄性小鼠，即CD4+CD25+ 成年雌性小鼠的调节性T细胞数量和功能降低。这个 这项拨款提案的中心假设是性类固醇介导了 CD4+CD25+调节性T细胞的性别差异 影响自身免疫性疾病差异表达的机制 女性对抗男性。以下具体目标旨在测试这一点 假设：I)女性和女性的CD4+CD25+调节性T细胞的特征 雄性小鼠；2)性激素对CD4+CD25+调节性T细胞的影响分析 细胞；以及3)解剖间隔的鉴定(S)对 影响CD4+CD25+调节性T细胞的性类固醇。结果是 这些研究将提供重要信息，可能导致 预防和治疗自身免疫疾病的新疗法的发展 疾病。

DESCRIPTION (provided by applicant): Many autoimmune diseases are much more prevalent in women compared to men, and include multiple sclerosis, arthritis and systemic lupus erythematosus. Although the reason for this difference is not currently known, the sex hormones are likely to play a significant role. A population of naturally occurring regulatory T cells, CD4+CD25+ regulatory T cells, has recently been described that is responsible for controlling autoimmune disease in mice. Elimination of this population in mice results in severe multi-organ autoimmune diseases. A homologous population has been found in humans that appears to express similar functional properties, at least, in in vitro assays. Our preliminary results indicate that both quantitative and qualitative differences exist in the CD4+CD25+ regulatory T cell population in adult, but not pre-pubertal, female versus male mice, i.e., CD4+CD25+ regulatory T cell numbers and function are decreased in adult female mice. The central hypothesis of this grant proposal is that sex steroids mediate the gender differences in CD4+ CD25+ regulatory T cells, and through this mechanism may influence the differential expression of autoimmune disease in females versus males. The following specific aims are designed to test this hypothesis: I) Characterization of CD4+CD25+ regulatory T cells in female and male mice; 2) Analysis of sex steroid influences on CD4+CD25+ regulatory T cells; and 3) Identification of the anatomical compartment(s) responsive to sex steroids that influences CD4+CD25+ regulatory T cells. The results of these studies will provide important information that can lead to the development of novel therapies for the prevention and treatment of autoimmune disease.