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

Autor:	Landuyt AE; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294., Klocke BJ; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294., Duck LW; Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294., Kemp KM; Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294., Muir RQ; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294., Jennings MS; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294., Blum SI; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294., Tse HM; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294., Lee G; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294., Morrow CD; Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35294., Elson CO; Division of Gastroenterology and Hepatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294., Maynard CL; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; craigmaynard@uabmc.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 30; Vol. 118 (13).
DOI:	10.1073/pnas.2018278118
Abstrakt:	Genome-wide association studies have identified ICOSLG , which encodes the inducible costimulator l igand (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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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