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

Immunity. 2018 Aug 21;49(2):342-352.e5. doi: 10.1016/j.immuni.2018.07.007. Epub 2018 Aug 7.

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.

MeSH terms

  • Animals
  • Antigens, CD / metabolism*
  • CX3C Chemokine Receptor 1 / metabolism*
  • Cells, Cultured
  • Colitis / immunology*
  • Colitis / pathology*
  • Dendritic Cells / immunology
  • Forkhead Transcription Factors / metabolism
  • Histocompatibility Antigens Class II / immunology
  • Interleukin-10 / immunology
  • Interleukin-1beta / immunology
  • Interleukin-23 Subunit p19 / immunology*
  • Interleukins / immunology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / pathology*
  • Macrophages / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / transplantation

Substances

  • Antigens, CD
  • CD223 antigen
  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Histocompatibility Antigens Class II
  • IL10 protein, mouse
  • IL1B protein, mouse
  • Il23a protein, mouse
  • Interleukin-1beta
  • Interleukin-23 Subunit p19
  • Interleukins
  • Interleukin-10
  • interleukin-22