title: The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity.
abstract: T helper 17 (Th17) cells protect against infection but also promote inflammation and autoimmunity. Therefore, the factors that govern Th17 cell differentiation are of special interest. The CD27 and CD70 costimulatory pathway impeded Th17 effector cell differentiation and associated autoimmunity in a mouse model of multiple sclerosis. CD27 or CD70 deficiency exacerbated disease, whereas constitutive CD27 signaling strongly reduced disease incidence and severity. CD27 signaling did not impact master regulators of T helper cell lineage commitment but selectively repressed transcription of the key effector molecules interleukin-17 (IL-17) and the chemokine receptor CCR6 in differentiating Th17 cells. CD27 mediated this repression at least in part via the c-Jun N-terminal kinase (JNK) pathway that restrained IL-17 and CCR6 expression in differentiating Th17 cells. CD27 signaling also resulted in epigenetic silencing of the Il17a gene. Thus, CD27 costimulation via JNK signaling, transcriptional, and epigenetic effects suppresses Th17 effector cell function and associated pathological consequences.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands. jonathanc@dmbr.ugent.be
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Coquet
authors.forename: Sabine
authors.initials: S
authors.lastname: Middendorp
authors.forename: Gerda
authors.initials: G
authors.lastname: van der Horst
authors.forename: Jop
authors.initials: J
authors.lastname: Kind
authors.forename: Elise A M
authors.initials: EA
authors.lastname: Veraar
authors.forename: Yanling
authors.initials: Y
authors.lastname: Xiao
authors.forename: Heinz
authors.initials: H
authors.lastname: Jacobs
authors.forename: Jannie
authors.initials: J
authors.lastname: Borst
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D053282:CD27 Ligand / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D054399:Receptors, CCR6 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*
chemical_list: D053282:CD27 Ligand; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D054399:Receptors, CCR6; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7