Intestinal tissue-resident memory T cells as mediators of inflammatory bowel disease and possible targets of etrolizumab therapy

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Inflammatory bowel diseases (IBD) comprise Crohn's disease (CD) and ulcerative colitis (UC). They are characterized by chronic relapsing inflammation of the intestinal tract and cause considerable morbidity. Treatment options are still insufficient and the precise pathogenesis is still not clear. However, it is commonly accepted that among other factors the intestinal immune system and especially T cells are crucial mediators of the diseases. They are recruited to the inflamed intestine in a highly complex process involving activation and priming, recirculation and so called homing. A whole variety of different T cell subpopulations with different functions and tasks is known. One of these is the recently described population of tissue-resident memory T cells (TRM cells), which resides in mucosal tissues in close contact to the epithelium without re-circulating and thus establishes immediate immunological memory in peripheral tissues. In the gut, these cells are characterized by expression of alphaEbeta7 integrin and CD69 and Hobit has been recently identified as an important transcriptional regulator of TRM cell differentiation. Although evidence from other models and diseases suggests a crucial role of TRM cells in immunologically mediated diseases, their function in IBD has not yet been addressed. Moreover, own data strongly support the notion that the drug etrolizumab (an anti-beta7 antibody) currently investigated in advanced clinical trials might interfere with tissue residency of TRM cells. Thus, the central hypothesis of this proposal is that TRM cells are crucial mediators of recurrent inflammatory flares in IBD and that the upcoming therapeutic agent etrolizumab might interfere with these cells. This hypothesis will be addressed by taking advantage of Hobit x Blimp-1 double knockout and CD69 knockout mice in both acute and chronic dextran sodium sulphate (DSS) colitis as well as in T cell transfer colitis models. Furthermore, the role of etrolizumab will be deciphered in vitro and in vivo in animal models and with intravital confocal microscopy. A potential role of pathogen-specific TRM cells in the mediation of acute inflammatory flare will be assessed in murine models and, finally, experiments in samples from IBD patients with or without etrolizumab therapy will reveal the importance of TRM cells in human IBD.