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

Abstract

Innate lymphoid cells (ILC) are a family of newly identified innate effector cells, and group 3 ILC (ILC3) is the major ILC in the gut that plays 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 in mice led to a marked reduction in colonic ILC3 populations at steady state. Citrobacter rodentium infection resulted in increased bacterial growth and high mortality in VDR^-/- mice compared with wild-type (WT) littermates because of impaired ILC3 immunity. VDR regulation of ILC3 was independent of T and B lymphocytes or gut microflora. Similar gut ILC3 defects were observed in VDRflox/flox;RORγt-Cre mice that carry VDR deletion only in ILC3, in Rag^1-/- mice transplanted with bone marrow cells from VDR^flox/flox;RORγt-Cre mice, or in Cyp27b1^-/- mice that cannot synthesize 1,25-dihydroxyvitamin D. Reconstitution of Cyp27b1^-/- mice with 1,25-dihydroxyvitamin D rescued the ILC3 defects. Mechanistically, vitamin D/VDR signaling is required for proper ILC3 proliferation; VDR or Cyp27B1 deletion led to marked decreases in colonic Ki67 ILC3 populations. In vitro studies confirmed that 1,25- dihydroxyvitamin D directly stimulated ILC3 proliferation. These observations indicate the vitamin D/VDR signaling is required for ILC3-mediated innate immunity in the gut.

Keywords: Vitamin D, Vitamin D receptor, innate lymphoid cell, Citrobacter rodentium