Pattern Recognition Receptor Signaling in Human Dendritic Cells is Enhanced by ICOS Ligand and Modulated by the Crohn’s Disease ICOSLG Risk Allele

• ICOS:ICOSL interactions on human DCs amplify PRR-induced signaling and cytokines
• Conserved arginines in the ICOSL tail recruit a PKC-RACK1-JNK signaling complex
• ICOSLG risk SNPs decrease ICOSL expression and PRR-induced signaling and cytokines
• The ICOSLG risk polymorphism is associated with an ileal Crohn’s disease phenotype

SummaryInflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune homeostasis and cytokine secretion. Multiple loci are associated with IBD, but a functional explanation is missing for most. Here we found that pattern-recognition receptor (PRR)-induced cytokine secretion was diminished in human monocyte-derived dendritic cells (MDDC) from rs7282490 ICOSLG GG risk carriers. Homotypic interactions between the costimulatory molecule ICOS and the ICOS ligand on MDDCs amplified nucleotide-binding oligomerization domain 2 (NOD2)-initiated cytokine secretion. This amplification required arginine residues in the ICOSL cytoplasmic tail that recruited the adaptor protein RACK1 and the kinases PKC and JNK leading to PKC, MAPK, and NF-κB activation. MDDC from rs7282490 GG risk-carriers had reduced ICOSL expression and PRR-initiated signaling and this loss-of-function ICOSLG risk allele associated with an ileal Crohn’s disease phenotype, similar to polymorphisms in NOD2. Taken together, ICOSL amplifies PRR-initiated outcomes, which might contribute to immune homeostasis.