IL-15 promotes inflammatory Th17 cells in the intestine

Ulcerative Colitis (UC) is a chronic gastrointestinal condition with high morbidity. While modern medical therapies have revolutionized the care of UC, 10-25% of patients fail medications and still progress to surgery. Thus, developing new treatments is a core problem in UC. T-cells, especially Th17 cells, are strongly linked with UC and are major targets of medications in UC. Tissue-resident memory T-cells (TRM) are a distinct class of T-cells that are highly enriched in the intestine, closely aligned with the microbiota, and are implicated in the pathogenesis of UC. Unlike circulating T-cells, TRM are difficult to target because they do not recirculate. Thus, we focused on cytokines like IL-15 which act as a tissue danger signal and regulate T-cells in situ. We found that the IL15 axis is upregulated in UC and predicts treatment response. IL-15 was redundant for Th17 differentiation but could activate terminally differentiated Th17 cells to promote intestinal inflammation. Finally, in CD4+ TRM from patients with UC, IL-15 upregulated RORC, the master transcription factor for Th17 cells, via a Janus Kinase (JAK)1 pathway. Thus, IL-15 promotes terminally differentiated inflammatory Th17 cells in the intestine raising the possibility that IL-15 may be a target for UC treatments.