CD4+ Tissue resident memory T-cells in Crohn's Disease

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ABSTRACT Crohn’s disease (CD) is a chronic condition with high morbidity and economic burden. Aberrant host responses to dysbiotic enteric microbiota are central to the pathogenesis of CD. Consistent with this concept, T-cell subsets closely aligned with the enteric microbiota, such as Th17 cells, are strongly implicated in CD. Although biologics have transformed the clinical management of CD, > 50% of patients eventually fail medical therapies and progress to surgery. Thus, characterizing pathogenic T-cell pathways is necessary to develop new therapies and identify prognostic biomarkers in CD. Tissue-resident memory T-cells (TRM) are a recently described subset of tissue-restricted non-circulating memory T-cells. They are antigen-specific and enriched at sites with high microbial burden, including the intestine. These features make TRM excellent candidates to link enteric dysbiosis with aberrant host responses. Indeed, we have reported that CD4+ TRM with a pathogenic Th17 signature are abundant in the intestine in CD and are enriched in CD compared to non-Inflammatory Bowel Disease (IBD) controls. Moreover, these enriched CD4+ TRM express the transcriptional repressor PR zinc finger domain (PRDM)1. In turn, knockdown of PRDM1 with silencing RNA results in the upregulation of the key cell trafficking molecule sphingosine 1 phosphate receptor 1 (S1PR1). As S1PR1 is by definition suppressed in TRM, this implies that PRDM1 promotes retention of pathogenic CD4+ TRM in the intestine in CD via transcriptional control of cell trafficking molecules. Furthermore, we find that IL-15 (which is enriched in CD), promotes the production of inflammatory cytokines by CD4+ TRM similar to the canonical pro-inflammatory cytokines IL-1β and IL-23. Finally, compatible with the possibility that the dysbiosis in CD drives pathogenic CD4+ TRM, humanized gnotobiotic IL-10-/- mice with CD-microbiota develop severe colitis relative to non-IBD control microbiota colonized counterparts. Moreover, the majority of colitogenic mucosal Th17 cells in these mice bear TRM markers. Thus, our data indicate that the CD microbiota induced pathogenic CD4+ TRM, which are regulated by PRDM1 and IL-15. Herein, we propose to 1) determine the mechanism and predictive capacity of PRDM1 in CD, 2) delineate the role of IL-15 in CD4+ TRM and 3) using humanized gnotobiotic mice colonized with microbiota from CD patients and healthy controls, define the extent to which CD microbiota induces pathogenic CD4+ TRM.