https://www.pnas.org/content/118/13/e2018278118
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.
