新型T细胞亚群exFoxp3的功能研究

exFoxp3细胞是由申请者率先在小鼠体内发现的一种新型CD4+T细胞亚群，该亚群曾经表达过调节性T细胞（Treg）的中心转录因子Foxp3及许多重要表面受体，并能分泌多种细胞因子，具有效应/记忆性T细胞的表型。目前exFoxp3细胞在体内免疫应答中扮演的角色还不清楚。我们已发表的工作显示exFoxp3细胞与Treg有部分重叠的T细胞受体库，exFoxp3可能同Treg一样具有自身反应性；并且在自发性I型糖尿病NOD小鼠的胰脏中有大量exFoxp3细胞的富集，提示该细胞可能在自身免疫疾病中起重要作用。为了深入研究exFoxp3亚群在T细胞免疫应答中的功能，本项目拟构建新型转基因小鼠选择性的在体内剔除exFoxp3细胞，探讨该亚群在I型糖尿病、自身免疫性脑脊髓炎及疫苗接种模型中的作用。该研究将深化我们对适应性免疫应答的认识，为临床多种疾病的治疗提供新思路。

Regulatory T cells (T(reg) cells) are central to the maintenance of immune homeostasis. We have demonstrated that a substantial percentage of cells had transient or unstable expression of the transcription factor Foxp3. These 'exFoxp3' T cells had an activated-memory T cell phenotype and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers were higher in inflamed tissues in autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid onset of diabetes. Finally, analysis of the T cell receptor repertoire suggested that exFoxp3 cells developed from both natural and adaptive T(reg) cells. Thus, exFoxp3 cells might play an important role in autoimmune disease pathogenesis. In this study, we propose to explore the function of exFoxp3 by using a new technique to deplete exFoxp3 cells in vivo. The result might have an important therapeutic application in a variety of disease settings ranging from autoimmunity to cancer and infectious disease.