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CD4+ tissue-resident memory T-cells expand and are a major source of mucosal tumor necrosis factor α in active Crohn's Disease.

S. Bishu,M. El Zaatari,A. Hayashi,G. Hou,Nicole Bowers,J. Kinnucan,Beth Manoogian,Michelle M. Muza-Moons,Min Zhang,H. Grasberger,Charlie Bourque,W. Zou,P. Higgins,J. Spence,R. Stidham,N. Kamada,J. Kao

Published 2019 in Journal of Crohn's & Colitis

ABSTRACT

Background and Aims Tumor 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 defense 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 characterize 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 that 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. Conclusion CD4+ TRM cells are expanded in CD and are a major source of TNFα, suggesting 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.

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