ICOS ligand and IL-10 synergize to promote host-microbiota mutualism

Proc Natl Acad Sci U S A. 2021 Mar 30;118(13):e2018278118. doi: 10.1073/pnas.2018278118.

Abstract

Genome-wide association studies have identified ICOSLG, which encodes the inducible costimulator ligand (ICOSLG or ICOSL) as a susceptibility locus for inflammatory bowel disease. ICOSL has been implicated in the enhancement of pattern recognition receptor signaling in dendritic cells, induction of IL-10 production by CD4 T cells, and the generation of high-affinity antibodies to specific antigens-all of which can potentially explain its involvement in gastrointestinal inflammation. Here, we show that murine ICOSL deficiency results in significant enrichment of IL-10-producing CD4 T cells particularly in the proximal large intestine. Transient depletion of IL-10-producing cells from adult ICOSL-deficient mice induced severe colonic inflammation that was prevented when mice were first treated with metronidazole. ICOSL-deficient mice displayed reduced IgA and IgG antibodies in the colon mucus and impaired serum antibody recognition of microbial antigens, including flagellins derived from mucus-associated bacteria of the Lachnospiraceae family. Confirming the synergy between ICOSL and IL-10, ICOSL deficiency coupled with CD4-specific deletion of the Il10 gene resulted in juvenile onset colitis that was impeded when pups were fostered by ICOSL-sufficient dams. In this setting, we found that both maternally acquired and host-derived antibodies contribute to the life anti-commensal antibody repertoire that mediates this protection in early life. Collectively, our findings reveal a partnership between ICOSL-dependent anti-commensal antibodies and IL-10 in adaptive immune regulation of the microbiota in the large intestine. Furthermore, we identify ICOSL deficiency as an effective platform for exploring the functions of anti-commensal antibodies in host-microbiota mutualism.

Keywords: ICOSL; IL-10; anti-commensal antibodies; microbiota.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Bacterial / immunology
  • Antigens, Bacterial / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Colon / immunology
  • Colon / microbiology
  • Colon / pathology
  • Disease Models, Animal
  • Female
  • Gastrointestinal Microbiome / immunology*
  • Host Microbial Interactions / immunology
  • Humans
  • Inducible T-Cell Co-Stimulator Ligand / genetics
  • Inducible T-Cell Co-Stimulator Ligand / metabolism*
  • Inducible T-Cell Co-Stimulator Protein / genetics
  • Inducible T-Cell Co-Stimulator Protein / metabolism
  • Inflammatory Bowel Diseases / immunology*
  • Inflammatory Bowel Diseases / microbiology
  • Inflammatory Bowel Diseases / pathology
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Signal Transduction / immunology
  • Symbiosis / immunology

Substances

  • Antibodies, Bacterial
  • Antigens, Bacterial
  • IL10 protein, mouse
  • Icos protein, mouse
  • Icosl protein, mouse
  • Inducible T-Cell Co-Stimulator Ligand
  • Inducible T-Cell Co-Stimulator Protein
  • Interleukin-10