LAG3+ Regulatory T Cells Restrain Interleukin-23-Producing CX3CR1+ Gut-Resident Macrophages during Group 3 Innate Lymphoid Cell-Driven Colitis

Abstract

Interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (ILC3) maintains gut homeostasis but can also promote inflammatory bowel disease (IBD). The regulation of ILC3-dependent colitis remains to be elucidated. Here we show that Foxp3 regulatory T cells (Treg cells) prevented ILC3-mediated colitis in an IL-10-independent manner. Treg cells inhibited IL-23 and IL-1β production from intestinal-resident CX3CR1 macrophages but not CD103 dendritic cells. Moreover, Treg cells restrained ILC3 production of IL-22 through suppression of CX3CR1 macrophage production of IL-23 and IL-1β. This suppression was contact dependent and was mediated by latent activation gene-3 (LAG-3)-an immune checkpoint receptor-expressed on Treg cells. Engagement of LAG-3 on MHC class II drove profound immunosuppression of CX3CR1 tissue-resident macrophages. Our study reveals that the health of the intestinal mucosa is maintained by an axis driven by Treg cells communication with resident macrophages that withhold inflammatory stimuli required for ILC3 function.

Indole-3-carbinol prevents colitis and associated microbial dysbiosis in an IL-22–dependent manner

“…Cells from the LP fraction were isolated as previously described (24). IL-22 production by immune cells in the LP were phenotyped using flow cytometry (BD FACs Celesta) based on a previous reports (95). The gating strategy is summarized in Supplemental Figure 13.…”

Treg Cells: A LAGging Hand Holds the Double-Edged Sword of the IL-23 Axis

“…Intestinal Treg cells suppress colitis; yet the mechanisms behind the intricate pathways involved in this process remain largely unknown. In this issue of Immunity, Bauché et al (2018) show that Treg cells engage MHCII on CX 3 CR1 + macrophages via LAG3. This indirectly reduces IL-22 mediated colonic inflammation.…”

Liver-Resident NK Cells Control Antiviral Activity of Hepatic T Cells via the PD-1-PD-L1 Axis

“…Moreover, compared with cNK cells, LrNK cells had higher expression of CD39, CD73, and LAG3 ( Figures 1D and 1E), which are associated with immunosuppressive functions of regulatory T cells (Bauché et al, 2018;Deaglio et al, 2007;Huang et al, 2004). Although transcripts of PD-L2 and inducible co-stimulator (ICOS) ligand (ICOSL) were enriched in LrNK cells, flowcytometry analysis showed undetectable surface expression ( Figures 1C-1E).…”