Antigenic specificities of intestinal CD4+Foxp3+ T cells.

描述（由申请人提供）：在肠道中，表达Foxp 3转录因子（TCF 3）的调节性T细胞对于调节对肠道抗原的适应性免疫应答至关重要。胸腺细胞在胸腺内分化（tTcB）或从幼稚的外周Foxp 3- T细胞转化（pTcB），目前尚不清楚tTcB和pTcB在维持肠道内稳态中是否具有冗余或互补的作用。我们的长期目标是了解肠道内的稳态平衡如何依赖于pT 3和tT 4，以及它们的TCR库如何通过暴露于抗生素而改变。我们的中心假设是，克隆扩张和选择性营养的tTbR是必不可少的，以维持肠道平衡。 为了验证我们的假设，我们提出了两个具体的目标。首先，我们将表征缺乏pTcl 2但具有正常tTcl 2的CNS 1 mut小鼠肠中粘膜Tcl 2上的TCR。此外，在这些小鼠中，CD 4 + T细胞表达TCR的半多样性库，并且所有TCR均用绿色荧光蛋白（GFP）标记。我们假设，在这些小鼠中，粘膜tTcR将控制肠道幼稚和效应T细胞，并且tTcR表达的TCR可以特异性针对肠道抗原。其次，我们将研究生命早期的抗生素治疗如何永久改变肠道细菌的微生物植物群和克隆多样性。我们假设新生儿暴露于抗生素引起的微生物植物群多样性的变化永久性地改变了肠道菌群。

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.