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Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis.

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2018

Nat Commun. 2018 Mar 16;9(1):1102. doi: 10.1038/s41467-018-03495-3.

Calcineurin-mediated IL-2 production by CD11chighMHCII+ myeloid cells is crucial for intestinal immune homeostasis.

A Mencarelli;HJ Khameneh;J Fric;M Vacca;S El Daker;B Janela;JP Tang;S Nabti;A Balachander;TS Lim;F Ginhoux;P Ricciardi-Castagnoli;A Mortellaro

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Singapore, 138648, Singapore. Program in Emerging Infectious Diseases, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore, 169857, Singapore. Center for Translational Medicine (CTM), International Clinical Research Center (ICRC), 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. Cancer Science Institute of Singapore (CSI), National University of Singapore (NUS), 14 Medical Drive, Singapore, 117599, Singapore. Toscana Life Science Foundation, Via Fiorentina 1, 53100, Siena, Italy. San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milan, Italy. mortellaro.alessandra@hsr.it.

Service type: Knockout mice

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 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.

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