Background and Aims Tumour necrosis factor [TNF]α- and IL-17A-producing T cells are implicated in Crohn’s disease [CD]. Tissue-resident memory T [TRM] cells are tissue-restricted T cells that are regulated by PR zinc finger domain 1 [PRDM1], which has been implicated in pathogenic Th17 cell responses. TRM cells provide host defence but their role in CD is unknown. We thus examined CD4+ TRM cells in CD. Methods Colon samples were prospectively collected at endoscopy or surgery in CD and control subjects. Flow cytometry and ex vivo assays were performed to characterise CD4+ TRM cells. Results CD4+ TRM cells are the most abundant memory T cell population and are the major T cell source of mucosal TNFα in CD. CD4+ TRM cells are expanded in CD and more avidly produce IL-17A and TNFα relative to control cells. There was a unique population of TNFα+IL-17A+ CD4+ TRM cells in CD which are largely absent in controls. PRDM1 was highly expressed by CD4+ TRM cells but not by other effector T cells. Suppression of PRDM1 was associated with impaired induction of IL17A and TNFA by CD4+ TRM cells Conclusions CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting that they are important in CD. PRDM1 is expressed by TRM cells and may regulate their function. Collectively, this argues for prospective studies tracking CD4+ TRM cells over the disease course.

Tissue-resident memory T cells (T RM cells) are a novel population of tissue-restricted antigen-specific T cells. T RM cells are induced by pathogens and promote host defense against secondary infections. Although T RM cells cannot be detected in circulation, they are the major memory CD4 ϩ and CD8 ϩ T-cell population in tissues in mice and humans. Murine models of CD8 ϩ T RM cells have shown that CD8 ϩ T RM cells maintain tissue residency via CD69 and though tumor growth factor ␤-dependent induction of CD103. In contrast to CD8 ϩ T RM cells, there are few models of CD4 ϩ T RM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4 ϩ T RM cells. Citrobacter rodentium is known to induce IL-17 ϩ and IL-22 ϩ CD4 ϩ T cells (T h 17 and T h 22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22 ϩ cells in the colon 3 months after C. rodentium infection are CD4 ϩ T cells. This collectively suggests that C. rodentium may induce CD4 ϩ T RM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A ϩ CD4 ϩ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4 ϩ T RM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4 ϩ T RM cells can promote host defense.