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

Andrea Mencarelli, Hanif Javanmard Khameneh, Jan Fric, Maurizio Vacca, Sary El Daker, Baptiste Janela, Jing Ping Tang, Sabrina Nabti, Akhila Balachander, Tong Seng Lim, Florent Ginhoux, Paola Ricciardi-Castagnoli and Alessandra Mortellaro ()
Additional contact information
Andrea Mencarelli: Agency for Science, Technology and Research (A*STAR)
Hanif Javanmard Khameneh: Agency for Science, Technology and Research (A*STAR)
Jan Fric: Agency for Science, Technology and Research (A*STAR)
Maurizio Vacca: Agency for Science, Technology and Research (A*STAR)
Sary El Daker: Institut Pasteur
Baptiste Janela: Agency for Science, Technology and Research (A*STAR)
Jing Ping Tang: Agency for Science, Technology and Research (A*STAR)
Sabrina Nabti: Agency for Science, Technology and Research (A*STAR)
Akhila Balachander: Agency for Science, Technology and Research (A*STAR)
Tong Seng Lim: Agency for Science, Technology and Research (A*STAR)
Florent Ginhoux: Agency for Science, Technology and Research (A*STAR)
Paola Ricciardi-Castagnoli: Agency for Science, Technology and Research (A*STAR)
Alessandra Mortellaro: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03495-3

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