Antigenic specificities of intestinal CD4+Foxp3+ T cells.

描述(申请人提供)：在肠道中，表达Foxp3转录因子(Tregs)的调节性T细胞对于调节对共生抗原的适应性免疫反应至关重要。Tregs在胸腺中分化(TTregs)或从幼稚的外周Foxp3-T细胞转化(PTregs)。目前尚不清楚tTregs和pTregs在维持肠道内环境稳定方面是否具有多余或互补的作用。我们的长期目标是了解肠道内的动态平衡如何依赖于pTregs和tTregs，以及它们的TCR谱系如何因接触抗生素而改变。我们的中心假设是tTregs的克隆扩张和选择性营养对于维持肠道平衡是必不可少的。 为了检验我们的假设，我们提出了两个具体目标。首先，我们将描述缺乏pTregs但tTregs正常的CNS1突变小鼠肠道粘膜Tregs上的TCRs。此外，在这些小鼠中，CD4T细胞表达半多样化的TCRs，所有Tregs都被绿色荧光蛋白(GFP)标记。我们推测，在这些小鼠中，粘膜中的tTregs将控制肠道的NAV和�效应T细胞，并且tTregs表达的TCRs可能是共生抗原的特异性。其次，我们将研究生命早期的抗生素治疗如何永久性地改变肠道微生物区系和克隆多样性。我们假设，新生儿接触抗生素引起的微生物菌群多样性的变化永久性地改变了肠道tTregs的谱系。

DESCRIPTION (provided by applicant): In the intestine, regulatory T cells that express Foxp3 transcription factor (Tregs) are critical for the regulation of adaptive immune response to commensal antigens. Tregs differentiate in the thymus (tTregs) or convert from naive, peripheral Foxp3- T cells (pTregs).It is currently unclear if tTregs and pTregs have redundant or complimentary role in maintenance of intestinal homeostasis. Our long term goal is to understand how the homeostatic balance in the intestine depends on pTregs and tTregs, and how their TCR repertoires can change by exposure to antibiotics. Our central hypothesis is that clonal expansions and selective trophism of tTregs are essential to sustain intestinal equilibrium. To test our hypothesis we propose two specific aims. First we will characterize TCRs on mucosal Tregs in the intestine of CNS1mut mice that lack pTregs but have normal tTregs. In addition, in these mice CD4+ T cells express semi diverse repertoire of TCRs and all Tregs are labeled with green fluorescent protein (GFP). We hypothesize that in these mice mucosal tTregs will control intestinal na�ve and effector T cells, and that TCRs expressed by tTregs can be specific to commensal antigens. Second, we will investigate how antibiotic treatment early in life can permanently change microbial flora and clonal diversity of intestinal Tregs. We hypothesize that changes in the diversity for microbial flora induced by neonatal exposure to antibiotics permanently alter repertoire of intestinal tTregs.