Vitamin D/Vitamin D Receptor Signaling Is Required for Normal Development and Function of Group 3 Innate Lymphoid Cells in the Gut

Group 3 innate lymphoid cells (ILC3) play key roles in protective immunity and mucosal barrier maintenance. Here we showed that vitamin D/vitamin D receptor (VDR) signaling regulates gut ILC3. VDR deletion or 1,25-dihydroxyvitamin D deficiency in mice led to a marked reduction in colonic ILC3 populations at steady state and impaired ILC3 responses following Citrobacter rodentium infection, resulting in substantial increases in intestinal bacterial growth and mouse mortality. VDR regulation of ILC3 was independent of T and B lymphocytes or gut microflora. Correction of 1,25-dihydroxyvitamin D deficiency rescued the ILC3 defects. Mechanistically, VDR deletion or 1,25-dihydroxyvitamin D deficiency markedly reduced colonic Ki67(+) ILC3 populations, and in vivo and in vitro studies confirmed that vitamin D hormone directly stimulated ILC3 proliferation. Therefore, vitamin D/VDR signaling is required for ILC3-mediated innate immunity through regulation of ILC3 proliferation.