IL-15 Promotes Inflammatory Th17 Cells in the Intestine

Ulcerative colitis (UC) is a chronic gastrointestinal condition with high morbidity. Modern therapies have revolutionized the care of UC, but 10% to 25% of patients do not respond to treatments and many progress to surgery. Thus, developing new treatments remains an important goal in UC. T cells, especially T helper 17 (Th17) cells, are linked with the pathogenesis of UC and are thought to be major targets of medications in UC. Therefore, we considered cytokines that may regulate pathogenic T cells in UC, focusing on cytokines that regulate T cells in tissue, as the intestinal microenvironment contains specialized noncirculating T cell subsets. Using public sequencing datasets, we identified that the IL15 axis is upregulated in UC and CD4+ T cells that express the specificity conferring receptor for IL-15 (IL-2RB) exhibit a pathogenic Th17 signature. Using a combination of murine models and human biospecimens, we verified that pathogenic Th17 cells express IL-2RB. IL-15 was redundant for Th17 differentiation, but IL-15 could activate terminally differentiated Th17 cells in the colon in a JAK1-dependent manner. Thus, we found that the IL15 axis is upregulated in UC and that IL-15 can activate inflammatory Th17 cells in the colon, raising the possibility that IL-15 is a potential target for UC treatments.