Intestinale gewebsansässige Gedächtnis-T-Zellen als Mediatoren chronisch entzündlicher Darmerkrankungen und potentielle Zielstrukturen von Therapie mit Etrolizumab
Zusammenfassung der Projektergebnisse
Inflammatory bowel diseases (IBDs) arise from a complex interplay of environmental and host factors critically involving the intestinal immune system. T cells are a central part in this process. However, although the role of so-called tissue resident memory T (TRM) cells had previously been characterized in host defense, their role in IBDs had been unclear. In mice, Hobit and Blimp-1 had been identified as important transcription factors driving TRM commitment. Therefore, the central hypothesis of this project was that tissue resident memory T (TRM) cells are crucial mediators of pathogenesis in experimental colitis and IBD and that the upcoming therapeutic agent etrolizumab (anti-beta7) might interfere with these cells. Thus, the objective of this project was to characterize the functional role of TRM cells in experimental colitis and human IBD. The key findings of the project were that CD69+CD103+ TRM cells are increased in the colon of patients with CD and UC compared with healthy controls. Moreover, such cells accumulated in the tissue of patients over the course of the disease. Importantly, in a prospective analysis, flare-free survival of IBD patients with high numbers of TRM cells was substantially shorter than in patients with low numbers of TRM cells. Consistently, mice depleted from TRM cells via application of diphtheria toxin in mice expressing the diphtheria toxin receptor under the control of the Hobit promotor or via local ligation of P2X7R by NAD were protected from T cell transfer and TNBS colitis, respectively. T cell transfer colitis was clearly less pronounced after transfer of Hobit and Blimp-1 double knockout T cells to lymphopenic recipients compared with transfer of Hobit and Blimp-1 competent cells. Similarly, DSS colitis and TNBS colitis in Hobit and Blimp-1 double knockout mice was less severe than in wild-type controls. Mechanistically, RNA sequencing identified a differential regulation of genes controlling the recruitment of innate and adaptive immune cells. Accordingly, the expression of several chemotactic agents in Hobit and Blimp-1-deficient settings was significantly reduced and in vitro recruitment of monocytes was decreased. Consistently, pro-inflammatory cytokines released from innate immune cells and downstream cytokines released from pro-inflammatory T cell subpopulations were substantially reduced in the lamina propria in a Hobit and Blimp-1-deficient context. Together, this argued for an adaptive-innate crosstalk mechanism originating from TRM cells and governing broad immune cell recruitment and activation resulting in a pro-inflammatory environment. In conclusion, the data identified TRM cells as crucial mediators of the pathogenesis of experimental colitis and IBD and suggest that these cells might be promising future targets of therapy.
Projektbezogene Publikationen (Auswahl)
- Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut. Gastroenterology 2017; 153:989-900
Zundler S, Klingberg A, Schillinger D, et al.
(Siehe online unter https://doi.org/10.1053/j.gastro.2017.07.022) - Hobit- and Blimp-1-driven CD4+ tissue resident memory T cells control chronic intestinal inflammation. Nature Immunology, Vol. 20. 2019, pp. 288–300.
Zundler S, Becker E, Spocinska M, et al.
(Siehe online unter https://doi.org/10.1038/s41590-018-0298-5)
