ROLE OF TCR SPECIFICITY IN SELECTING IL-10 PRODUCING CELLS IN THE COLON

描述（由申请人提供）：结肠耐受性丧失是一个重要的临床问题，因为它被认为会导致炎症性肠病。T细胞产生IL-10在维持结肠耐受性中起重要作用。然而，目前尚不清楚IL-10是由T细胞对可能来自细菌的特定抗原产生反应，还是通过非抗原特异性刺激（如细胞因子）在结肠T细胞上表达。本提案的目的是通过对固定TCR¿转基因小鼠的TRAV14 TCRa库进行测序，来解决抗原特异性在选择结肠中Tr1和IL-10+调节性T （Treg）细胞中是否重要。如果我们的假设是正确的，我们将观察到IL-10+亚群利用一组独特的TCR，这可能有助于生成Tr1或IL-10+ Treg细胞发育的TCR转基因模型。利用TCR测序数据，我们将选择常见的Tr1和IL-10+ Treg TCR来确定它们是否识别细菌，以及它们是否促进胸腺或外周T细胞的发育。TCR可重复性地导致外周Tr1和IL-10+ Treg细胞发育，然后可用于生成TCR转基因模型，以研究IL-10在T细胞中的调节。因此，这些研究将增加我们对产生IL-10的T细胞亚群如何产生的理解，这可能有助于开发针对人类疾病的新疗法。

DESCRIPTION (provided by applicant): Loss of colonic tolerance is a significant clinical problem, as it is thought to result in inflammatory bowel disease. The production of IL-10 by T cells plays an important role in maintaining colonic tolerance. However, it is unclear whether IL-10 is produced by T cells responding to specific antigens potentially derived from bacteria, or is expressed on colonic T cells via non-antigen specific stimuli such as cytokines. The goal of this proposal is to address whether antigen specificity is important in selecting Tr1 and IL-10+ regulatory T (Treg) cells in the colon by sequencing the TRAV14 TCRa repertoire in fixed TCR¿ transgenic mice. If our hypothesis is correct, we will observe that the IL-10+ subsets utilize a unique set of TCRs, which may be useful for the generation of TCR transgenic models of Tr1 or IL-10+ Treg cell development. Using the TCR sequencing data, we will select common Tr1 and IL-10+ Treg TCRs to determine whether they recognize bacteria, and whether they facilitate thymic or peripheral T cell development. TCRs which reproducibly result in peripheral Tr1 and IL-10+ Treg cell development can then be used to generate TCR transgenic models to study IL-10 regulation in T cells. Thus, these studies will increase our understanding regarding how the IL-10 producing T cell subset is generated, which may be useful for developing novel therapies for human disease. PUBLIC HEALTH RELEVANCE: Inflammatory bowel disease (IBD) afflicts approximately 0.1 - 0.2% of the general population, and causes significant morbidity and mortality from abdominal pain, weight loss, diarrhea, bleeding, and cancer. IL-10 is an important molecule required to prevent spontaneous colonic inflammation produced by T cells. The goal of this proposal is to understand how IL-10 expression is induced within T cells, which may lead to the development of novel therapies for IBD.