Calcineurin-mediated IL-2 production by CD11c^highMHCII⁺ myeloid cells is crucial for intestinal immune homeostasis.

Abstract

The intestinal immune system can respond to invading pathogens yet maintain immune tolerance to self-antigens and microbiota. Myeloid cells are central to these processes, but the signaling pathways that underlie tolerance versus inflammation are unclear. Here we show that mice lacking Calcineurin B in CD11c^highMHCII⁺ cells (Cnb1 ^CD11c mice) spontaneously develop intestinal inflammation and are susceptible to induced colitis. In these mice, colitis is associated with expansion of T helper type 1 (Th1) and Th17 cell populations and a decrease in the number of FoxP3⁺ regulatory T (Treg) cells, and the pathology is linked to the inability of intestinal Cnb1-deficient CD11c^highMHCII⁺ cells to express IL-2. Deleting IL-2 in CD11c^highMHCII⁺ cells induces spontaneous colitis resembling human inflammatory bowel disease. Our findings identify that the calcineurin-NFAT-IL-2 pathway in myeloid cells is a critical regulator of intestinal homeostasis by influencing the balance of inflammatory and regulatory responses in the mouse intestine.