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

• Applicant: Dr. Helena Kiefel
• Subject Area: Immunology
• Term: from 2011 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 203229134

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.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Eugene C. Butcher