ILC3-derived OX40L is essential for homeostasis of intestinal Tregs in immunodeficient mice

Abstract

OX40L is one of the co-stimulatory molecules that can be expressed by splenic lymphoid tissue inducer (Lti) cells, a subset of group 3 innate lymphoid cells (ILC3s). OX40L expression in subsets of intestinal ILC3s and the molecular regulation of OX40L expression in ILC3s are unknown. Here, we showed intestinal ILC3s marked as an OX40L high population among all the intestinal leukocytes and were the dominant source of OX40L in Rag1 -/mice. All ILC3 subsets expressed OX40L, and NCR -ILC3s were the most abundant source of OX40L. The expression of OX40L in ILC3s could be upregulated during inflammation. In addition to tumor necrosis factor (TNF)-like cytokine 1A (TL1A), which has been known as a trigger for OX40L, we found that Poly (I:C) representing viral stimulus promoted OX40L expression in ILC3s via a cell-autonomous manner. Furthermore, we demonstrated that IL-7-STAT5 signaling sustained OX40L expression by ILC3s. Intestinal regulatory T cells (Tregs), most of which expressed OX40, had defective expansion in chimeric mice, in which ILC3s were specifically deficient for OX40L expression. Consistently, co-localization of Tregs and ILC3s was found in the cryptopatches of the intestine, which suggests the close interaction between ILC3s and Tregs. Our study has unveiled the crosstalk between Tregs and ILC3s in mucosal tissues through OX40-OX40L signaling, which is crucial for the homeostasis of intestinal Tregs.

Th1 responses in vivo require cell-specific provision of OX40L dictated by environmental cues

“…In the response to Salmonella-2W1S, deletion of OX40L using the Rorc cre resulted in the loss of IFNγ-producing Th1 CD4 T cells in both the draining lymphoid tissue and the effector tissue (colon). While T cell provision of OX40L cannot be excluded, these data are consistent with ILC3 OX40L expression critical for intestinal T cell responses, significantly developing previous studies using immunodeficient mice 50,55 where ILC frequencies are grossly perturbed 31 . The lack of a role for ILC3s in the splenic response to Lm-2W1S may reflect the acute response or simply perhaps the very low frequency of ILC3 in the spleen and the lack of clear clusters of ILC3, as seen in the intestine and their draining LNs 30 .…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…310 The significance of ILC3 cells in host-microbial interactions was clarified in a study in which their depletion and the resulting abrogation of Treg differentiation resulted in the loss of host immune tolerance. 311 To maintain tolerance to commensal bacteria, MHCII-expressing ILC3 cells elicit the apoptosis of commensal microbiome-reactive CD4 + T cells and impede commensal-specific T cell responses. 312 Microbial sensing and macrophage-generated IL-1β stimulate the secretion of ILC3derived granulocyte-macrophage colony-stimulating factor, which promotes Treg development and immune tolerance via IL-10 generation by DC and monocytes.…”

“…315 Notably, OX40L is a ligand for OX40 that is expressed in mucosal ILC3 cells and in intestinal Treg cells, thereby serving as a favorable regulator of intestinal Treg homeostasis in Rag1 −/− mice. 311 In addition, Mincle (the Syk-coupled C-type lectin receptor) in intestinal DCs triggers IL-22 generation by ILC3 cells in response to mucosal colonization commensals in the PPs. 316 Intriguingly, the microbiome-ILC3 partnership also involves glial cells in the lamina propria to accelerate the intestinal steady state.…”

Metabolic Regulation of Group 3 Innate Lymphoid Cells and Their Role in Inflammatory Bowel Disease

“…Nevertheless, activation of DR3 contributes to the reduced abundance of ILC3s in a GM-CSF-and IL-23-dependent manner, which consequently exacerbates DSS-induced colitis in mice (79). OX40L expression by ILC3s has been demonstrated to be essential for homeostatic expansion of intestinal regulatory T cells (Tregs) in mice, and the expression of OX40L can be increased by TL1A and viral stimulation or inhibited by CD4 + T cells (80). However, TL1A-induced OX40L expression on MHCII + ILC3s promotes the activation of T-BET + Th1 cells, which is essential for chronic T-cell colitis in mice (78).…”