title: IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells.
abstract: Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T(FH)) cells. T(FH) cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T(FH) cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T(FH) cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T(FH) cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T(FH) cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.
authors.affiliation: Garvan Institute of Medical Research, Darlinghurst, Sydney NSW 2010, Australia. m.batten@garvan.org.au
authors.forename: Marcel
authors.initials: M
authors.lastname: Batten
authors.forename: Nandhini
authors.initials: N
authors.lastname: Ramamoorthi
authors.forename: Noelyn M
authors.initials: NM
authors.lastname: Kljavin
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Cox
authors.forename: Hart S
authors.initials: HS
authors.lastname: Dengler
authors.forename: Dimitry M
authors.initials: DM
authors.lastname: Danilenko
authors.forename: Patrick
authors.initials: P
authors.lastname: Caplazi
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Cecile
authors.initials: C
authors.lastname: King
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects; D018858:Germinal Center / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000276:immunology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013729:Terpenes; D018183:Transplantation Chimera / Q000276:immunology; D000098546:Interleukin-21
chemical_list: C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D013729:Terpenes; C009042:pristane; D000098546:Interleukin-21