Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn's disease ICOSLG risk allele.
Inflammatory 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.
Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06510, USA.
Matija
M
Hedl
Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06510, USA.
Amit
A
Lahiri
Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06510, USA.
Kaida
K
Ning
Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06510, USA.
Judy H
JH
Cho
Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT 06510, USA. Electronic address: clara.abraham@yale.edu.
Clara
C
Abraham
D002478:Cells, Cultured; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D004789:Enzyme Activation / Q000276:immunology; D019204:GTP-Binding Proteins / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011493:Protein Kinase C / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000276:immunology; D051192:Receptors, Pattern Recognition / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics
C556692:ICOS protein, human; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D016328:NF-kappa B; C429018:NOD2 protein, human; D009363:Neoplasm Proteins; D053473:Nod2 Signaling Adaptor Protein; C419368:RACK1 protein, human; D034741:RNA, Small Interfering; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D051192:Receptors, Pattern Recognition; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins