Vitamin A Controls the Presence of RORγ+ Innate Lymphoid Cells and Lymphoid Tissue in the Small Intestine

Abstract

Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR− and NCR+ ILC3 subsets in the small intestine of mice raised on a vitamin A–deficient diet. Additionally, the percentages of IL-22–producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR− ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A–deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid–related orphan receptor γt–Cre × RARα-DN mice had reduced numbers of NCR− and NCR+ ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid–related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines.

STAT1 Represses Cytokine-Producing Group 2 and Group 3 Innate Lymphoid Cells during Viral Infection

“…For ILC2, such targets include lipid mediators PGI 2 (inhibitory), PGD 2 (activating), and LTD 4 (activating) as well as cytokines including IL-33 and TSLP (3, 48–52). Retinoic acid has been shown to promote ILC3 in the gastrointestinal tract, and accordingly dietary modification of retinoic acid derivatives including vitamin A may present a viable therapeutic target (53). However, an effective and non-pathologic immune response often requires the coordinated activation and inhibition of multiple cell types.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Vitamin A deprivation results in a loss of intestinal ILC3 in adult mice, which can be reversed upon supplementation of diet with the vitamin A-derived metabolite retinoic acid. 44,45 Similarly, Ahr acts to sense soluble aromatic hydrocarbonspresent in the diet and produced by commensal bacteriaand is essential for the development of both LTi-like and NKp46 + ILC3, as well as IL-22 production. 14,27,28,[46][47][48][49][50][51] Together these signals tune ILC3 numbers and responses and establish bidirectional interactions between ILC3 and the commensal microbiota during the initial colonization of barrier tissue sites.…”

Innate lymphoid cells, mediators of tissue homeostasis, adaptation and disease tolerance

“…In addition to its role during ontogeny, RA has been shown to activate ILC3 and to promote their tissue repair function in adult mice. RA stimulates ILC3 by direct binding of its heterodimeric receptor/transcription factor to the Rorc and Il22 loci . Adult mice fed with a RA‐deprived diet or treated with an RAR inhibitor had reduced numbers of ILC3 and produced less IL‐22.…”