title: RORγt expression in Tregspromotes systemic lupus erythematosus via IL-17 secretion, alteration of Tregphenotype and suppression of Th2 responses.
abstract: Systemic lupus erythematosus (SLE) is a common autoimmune disorder with a complex and poorly understood immunopathogenesis. However, a pathogenic role for the T helper type 17 (Th17) axis was demonstrated by many studies, while regulatory T cells (Tregs) were shown to mediate protection. Recently, we and others characterized a novel and independent T cell population expressing both the Tregcharacteristic transcription factor forkhead box protein 3 (FoxP3) and the Th17-defining retinoic acid receptor-related orphan nuclear receptor γt (RORγt). Studies in a model of acute glomerulonephritis unveiled potent regulatory, but also proinflammatory, functions of RORγt+FoxP3+Tregs. This bi-functional nature prompted us to suggest the name 'biTregs'. Importantly, the pathogenic biTregeffects were dependent upon expression of RORγt. We thus aimed to evaluate the contribution of RORγt+FoxP3+biTregsto pristane-induced SLE and explored the therapeutic potential of interference with RORγt activation. Our analyses revealed expansion of IL-17 producing biTregsin a distinctive time-course and organ-specific pattern, coincident with the development of autoimmunity and tissue injury. Importantly, specific ablation of RORγt activation in endogenous biTregsresulted in significant amelioration of pristane-induced pulmonary vasculitis and lupus nephritis. As potential mechanisms underlying the observed protection, we found that secretion of IL-17 by biTregswas abrogated completely in FoxP3Cre× RORCfl/flmice. Furthermore, Tregsshowed a more activated phenotype after cell-specific inactivation of RORγt signalling. Finally, and remarkably, biTregswere found to potently suppress anti-inflammatory Th2 immunity in a RORγt-dependent manner. Our study thus identifies biTregsas novel players in SLE and advocates RORγt-directed interventions as promising therapeutic strategies.
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: M A
authors.initials: MA
authors.lastname: Kluger
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Nosko
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Ramcke
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Goerke
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: M C
authors.initials: MC
authors.lastname: Meyer
authors.affiliation: Institut für experimentelle Immunologie und Hepatologie, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wegscheid
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Luig
authors.affiliation: Institut für experimentelle Immunologie und Hepatologie, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Tiegs
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: R A K
authors.initials: RA
authors.lastname: Stahl
authors.affiliation: III Medizinische Klinik, Universitätsklinikum Eppendorf, Hamburg, Germany.
authors.forename: O M
authors.initials: OM
authors.lastname: Steinmetz
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D056724:Immunity, Humoral; D056747:Immunomodulation; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse
keywords: immunology; lupus nephritis; lymphocytes; systemic lupus; transcription factors