Die Expression eines G-Protein-gekoppelten Rezeptors für kurzkettige Fettsäuren auf intestinalen T-Zellen und seine Rolle in T-Zell-Trafficking und Kolitis
Zusammenfassung der Projektergebnisse
In the intestine efficient barrier immunity is closely linked to a highly tolerogenic environment towards food antigens and commensal bacteria. The G-protein-coupled receptor GPCR GPR43 and its agonist, short-chain fatty acids (SCFAs) has been shown to promote the migration of neutrophils to the small intestine (SI), but overall to contribute to an antiinflammatory state. GPR43-/- mice show worsened disease in animal models of arthritis and colitis. The beneficial role of GPR43 in colitis has largely been attributed to the GPR43- dependent expansion of regulatory T cells in response to SCFA. Other studies have shown that GPR43 on intestinal epithelial cells is critical for the generation of Th1 and Th17 cells in response to C. rodentium infections, supporting also an indirect role for GPR43 on intestinal immune cells. The goal of my studies was to investigate whether GPR43 acts as a gut homing receptor for T cells or maintains the balance between tolerogenic and pro-inflammatory immune responses by regulating proliferation or survival of T cell subsets in the gut associated lymphoid tissues (GALT) and the intestine. I was also interested in the role of GPR43 on dendritic cells, which have emerged as critical players in intestinal immunity. Our seminal microarray studies showed that GPR43 is expressed selectively on memory T cells in the small intestine, an expression pattern similar to the gut homing receptor CCR9. To study effects of GPR43 loss on intestinal immune cells, I used mixed bone marrow chimeras in which GPR43 deficient cells “compete” directly with wild type cells for survival, growth and trafficking signals. I could not corroborate a role for GPR43 as trafficking receptor for intestinal T cells but I discovered that GPR43 expression actually reduces the representation of memory T cells in the small intestine. Further dissection of intestinal T cell subsets revealed, that GPR43- deficient FoxP3+ and IL17+ cells were increased in the small intestinal lamina propria. GPR43-deficiency resulted also in an increased of migratory intestinal dendritic cells in the gutdraining mesenteric lymph nodes, which could be abolished by antibiotic treatment and rescued by propionate feeding. The observed effects were selective for T and dendritic cells of the gut and GALT, which correlates with the selective expression of the GPR43 gene in gut memory T cells and in CD103+CD11b+ (migratory) intestinal DC. In addition to the effects on intestinal immune cell subsets I further obtained evidence that GPR43 might have a global impact on the survival/reconstitution of bone marrow-derived myeloid progenitors. Furthermore the receptor seems to play a role in the recruitment of myeloid cells in response to Ang-2, without promoting further activation. Overall my studies support the role of GPR43 as an important immunoregulatory receptor. Understanding the global role of GPR43 in inflammatory responses will significantly help to clarify the mechanisms that contribute to immune tolerance and chronic inflammation.
Projektbezogene Publikationen (Auswahl)
- Intestinal T Cell Expression of a G-Protein-Coupled Receptor for Short Chain Fatty Acids: Role in T Cell Homeostasis and Colitis. Keystone Symposium, Inflammatory Diseases: Recent Advances in Basic and Translational Research and Therapeutic Treatments, 2014
Kiefel, H., Butcher, E.C.
- Taking TNFa-mediated regulation of MAdCAM1 in endothelial cells up a Notch. Annual Meeting of the German Society for Immunology, 2014
Kiefel, H., O’Hara, E., Lee, M., Pan, J., Butcher, E. C.
- Transcriptional programs of lymphoid tissue capillary and high endothelium reveal control mechanisms for lymphocyte homing. Nat. Immunology 2014 Oct;15(10):982-95
Lee, M., Kiefel, H., LaJevic, M.D., Macauley, M.S., O'Hara, E., Pan, J., Paulson, J.C., Butcher, E.C.
(Siehe online unter https://doi.org/10.1038/ni.2983)
