Interleukin-7 receptor pathway controls human T cell homing to the gut and predicts response to anti-TNFα therapy in IBD

Abstract

Abstract Background and aims Signaling networks perpetuating chronic gastrointestinal inflammation in Crohn’s disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD), remain unclear in man. Methods and results According to an analysis of nearly 500 patients with IBD and 100 controls, we report here that key transcripts of the IL-7 receptor (IL-7R) pathway accumulate in inflamed colon tissues of severe IBD patients not responding to either immunosuppressive/corticosteroids or anti-TNFα therapies. High expression of both IL-7R and IL-7R signaling signature transcripts in the colon before treatment are strongly associated with nonresponsiveness to anti-TNFα therapy. While in mice IL-7 is known to play a role in systemic inflammation, we found that in humans IL-7 also controls α4/β7 integrin expression and imprints gut-homing specificity on T cells. IL-7 receptor blockade in vivo reduced human T cell homing to the gut and colonic inflammation in humanized mouse models, and decreased production of IFNγ by colon explants from UC patients grown ex vivo. Conclusion Our findings suggest that the failure of current treatments for IBD, including anti-TNF, may occur at least in part by dysregulated IL-7R signaling and points to the IL-7R as a relevant novel therapeutic target and biomarker to fill an unmet need in clinical IBD detection and treatment.