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 CD11chighMHCII+ 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 CD11chighMHCII+ cells to express IL-2. Deleting IL-2 in CD11chighMHCII+ 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.

Cancer Science Institute of Singapore 14 Medical Drive Singapore 117599 Singapore

Center for Translational Medicine St Anne's University Hospital Pekarska 53 656 91 Brno Czech Republic

Institut Unité de Biologie des Populations Lymphocytaires Department of Immunology Institut Pasteur Paris 75015 France

Kwazulu Natal Research Institute for Tuberculosis and HIV Nelson R Mandela Medical School 719 Umbilo Rd Durban 4001 South Africa

Program in Emerging Infectious Diseases Duke National University of Singapore Graduate Medical School 8 College Road Singapore 169857 Singapore

San Raffaele Telethon Institute for Gene Therapy IRCCS San Raffaele Scientific Institute Via Olgettina 58 20132 Milan Italy

Singapore Immunology Network Singapore 138648 Singapore

Toscana Life Science Foundation Via Fiorentina 1 53100 Siena Italy

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Roles of IL-2 in bridging adaptive and innate immunity, and as a tool for cellular immunotherapy

Calcineurin inhibitors reduce NFAT-dependent expression of antifungal pentraxin-3 by human monocytes