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ICOS ligand and IL-10 synergize to promote host–microbiota mutualism
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
- Publisher :
- Proceedings of the National Academy of Sciences, 2021.
-
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.
- Subjects :
- CD4-Positive T-Lymphocytes
Male
0301 basic medicine
Colon
Inflammation
Inflammatory bowel disease
Inducible T-Cell Co-Stimulator Protein
Inducible T-Cell Co-Stimulator Ligand
Mice
03 medical and health sciences
0302 clinical medicine
Antigen
medicine
Animals
Humans
Intestinal Mucosa
Symbiosis
Mice, Knockout
Antigens, Bacterial
Multidisciplinary
Host Microbial Interactions
biology
Lachnospiraceae
Pattern recognition receptor
Biological Sciences
Inflammatory Bowel Diseases
medicine.disease
Antibodies, Bacterial
Gastrointestinal Microbiome
Interleukin-10
ICOS LIGAND
Disease Models, Animal
Interleukin 10
030104 developmental biology
Immunology
biology.protein
Female
Antibody
medicine.symptom
Signal Transduction
030215 immunology
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 118
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....1a9f82c70c2fa683aacb9a6bd1a9e0d5