Intestinal T cell expression of a G protein linked receptor for short chain fatty acids: role in T cell trafficking and colitis.

白细胞募集到炎症部位是建立有效免疫反应的关键步骤。然而，正如在炎症性肠病（IBD）中观察到的那样，不受控制的炎症反应会导致严重的组织损伤，并最终导致癌症的发生和进展。有益炎症反应和病理生理性炎症反应之间的密切联系导致了研究白细胞归巢到特定组织和炎症部位的基本机制的实质性动机。G蛋白偶联受体（GPCR） CCR9已被描述为T细胞归巢到小肠（SI）所需的主要趋化因子受体。然而，CD4+ T细胞已被证明使用ccr9依赖性和ccr9非依赖性机制进入SI固有层，这表明额外的gpcr在T细胞募集中的作用。最近的研究已经描述了GPCR GPR43及其激动剂短链脂肪酸（SCFAs）在白细胞向SI迁移中的功能，并暗示了GPR43在肠道炎症中的作用。此外，GPR43在SI记忆T细胞上的高表达表明，GPR43可能是介导不依赖ccr9的SI归巢的难以捉摸的GPCR。在这项研究中，我希望研究GPR43在CD4+记忆T细胞运输中的功能。首先，我将表征GPR43在淋巴细胞亚群上的表达，并研究它们在体外对scfa的趋化性。该研究的主要重点将是评估GPR43在SI体内淋巴细胞运输和定位中的作用。另一个需要解决的方面是CCR9和GPR43在SI T细胞定位中是否具有重叠或不同的功能。此外，由于肠道CD4+ T细胞与慢性肠道炎症有关，我希望通过IBD的实验模型来评估GPR43+ T细胞在这些异常炎症反应中的功能。

The recruitment of leukocytes to sites of inflammation is a critical step in establishing an effective immune response. However, uncontrolled inflammatory responses, as observed in inflammatory bowel disease (IBD), lead to severe tissue damage and can finally contribute to the initiation and progression of cancer. The close link between beneficial and pathophysiological inflammatory responses has led to substantial motivation to study the basic mechanisms underlying leukocyte homing to specific tissues and sites of inflammation. The G protein coupled receptors (GPCR) CCR9 has been described as the major chemokine receptor required for the homing of T cells to the small intestine (SI). However, CD4+ T cells have been shown to use both CCR9-dependent and CCR9-independent mechanisms of entry into the SI lamina propria, suggesting a role for additional GPCRs in T cell recruitment. Recent studies have described the function of the GPCR GPR43 and its agonist, short-chain fatty acids (SCFAs) in the migration of leukocytes to the SI and have implicated a role for GPR43 in intestinal inflammation. In addition, a high expression of GPR43 on SI memory T cells suggests that GPR43 may be the elusive GPCR that mediates CCR9-independent homing to the SI. In the proposed study I wish to investigate the function of GPR43 in the trafficking of CD4+ memory T cells. Initially, I will characterize the expression of GPR43 on lymphocyte subsets and study their chemotaxis towards SCFAs in vitro. A major focus of the study will be to assess the role of GPR43 in lymphocyte trafficking and localization in the SI in vivo. One additional aspect to be addressed is whether CCR9 and GPR43 have overlapping or distinct functions in SI T cell localization. Furthermore, as intestinal CD4+ T cells have been implicated in chronic intestinal inflammation, I wish to assess the function of GPR43+ T cells in these aberrant inflammatory responses using experimental models of IBD.