title: The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans.
abstract: IL-23 and Th17 cells are key players in tissue immunosurveillance and are implicated in human immune-mediated diseases. Genome-wide association studies have shown that the IL23R R381Q gene variant protects against psoriasis, Crohn's disease and ankylosing spondylitis. We investigated the immunological consequences of the protective IL23R R381Q gene variant in healthy donors. The IL23R R381Q gene variant had no major effect on Th17 cell differentiation as the frequency of circulating Th17 cells was similar in carriers of the IL23R protective (A) and common (G) allele. Accordingly, Th17 cells generated from A and G donors produced similar amounts of Th17 cytokines. However, IL-23-mediated Th17 cell effector function was impaired, as Th17 cells from A allele carriers had significantly reduced IL-23-induced IL-17A production and STAT3 phosphorylation compared to G allele carriers. Our functional analysis of a human disease-associated gene variant demonstrates that IL23R R381Q exerts its protective effects through selective attenuation of IL-23-induced Th17 cell effector function without interfering with Th17 differentiation, and highlights its importance in the protection against IL-23-induced tissue pathologies.
authors.affiliation: St John's Institute of Dermatology, King's College London and NIHR Biomedical Research Centre, London, United Kingdom.
authors.forename: Paola
authors.initials: P
authors.lastname: Di Meglio
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Cesare
authors.forename: Ute
authors.initials: U
authors.lastname: Laggner
authors.forename: Chung-Ching
authors.initials: CC
authors.lastname: Chu
authors.forename: Luca
authors.initials: L
authors.lastname: Napolitano
authors.forename: Federica
authors.initials: F
authors.lastname: Villanova
authors.forename: Isabella
authors.initials: I
authors.lastname: Tosi
authors.forename: Francesca
authors.initials: F
authors.lastname: Capon
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Ketty
authors.initials: K
authors.lastname: Peris
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
mesh_terms: D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D001120:Arginine / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007154:Immune System Diseases / Q000235:genetics*; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics*; D053759:Interleukin-23 / Q000378:metabolism / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D018123:Receptors, Interleukin / Q000235:genetics* / Q000502:physiology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D055815:Young Adult
chemical_list: C515500:IL23R protein, human; D053759:Interleukin-23; D018123:Receptors, Interleukin; D018698:Glutamic Acid; D001120:Arginine