title: Stat3 programs Th17-specific regulatory T cells to control GN.
abstract: A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified. We studied the function of Treg17 in the nephrotoxic nephritis (NTN) model of crescentic GN. The absence of Treg17 cells in Foxp3(Cre)×Stat3(fl/fl) mice resulted in the aggravation of NTN and skewing of renal and systemic immune responses toward Th17. Detailed analysis of Stat3-deficient Tregs revealed that the survival, activation, proliferation, and suppressive function of these cells remained intact. However, Tregs from Foxp3(Cre)×Stat3(fl/fl) mice lacked surface expression of the chemokine receptor CCR6, which resulted in impaired renal trafficking. Furthermore, aggravation of NTN was reversible in the absence of Th17 responses, as shown in CD4(Cre)×Stat3(fl/fl) mice lacking both Treg17 and Th17 cells, suggesting that Th17 cells are indeed the major target of Treg17 cells. Notably, immunohistochemistry revealed CCR6-bearing Treg17 cells in kidney biopsy specimens of patients with GN. CCR6 expression on human Treg17 cells also appears dependent on STAT3, as shown by analysis of Tregs from patients with dominant-negative STAT3 mutations. Our data indicate the presence and involvement of Stat3/STAT3-dependent Treg17 cells that specifically target Th17 cells in murine and human crescentic GN, and suggest the kidney-specific action of these Treg17 cells is regulated by CCR6-directed migration into areas of Th17 inflammation.
authors: III Medizinische Klinik.
authors: Malte A
authors: MA
authors: Kluger
authors: III Medizinische Klinik.
authors: Michael
authors: M
authors: Luig
authors: Institut für Experimentelle Hepatologie und Immunologie, Universitätsklinikum Eppendorf, Hamburg, Germany; and.
authors: Claudia
authors: C
authors: Wegscheid
authors: III Medizinische Klinik.
authors: Boeren
authors: B
authors: Goerke
authors: III Medizinische Klinik.
authors: Hans-Joachim
authors: HJ
authors: Paust
authors: III Medizinische Klinik.
authors: Silke R
authors: SR
authors: Brix
authors: Institut für Immunologie.
authors: Isabell
authors: I
authors: Yan
authors: Institut für Immunologie.
authors: Hans-Willi
authors: HW
authors: Mittrücker
authors: University Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors: Beate
authors: B
authors: Hagl
authors: University Children's Hospital, Ludwig Maximilians University, Munich, Germany.
authors: Ellen D
authors: ED
authors: Renner
authors: Institut für Experimentelle Hepatologie und Immunologie, Universitätsklinikum Eppendorf, Hamburg, Germany; and.
authors: Gisa
authors: G
authors: Tiegs
authors: Institut für Pathologie, and.
authors: Thorsten
authors: T
authors: Wiech
authors: III Medizinische Klinik.
authors: Rolf A K
authors: RA
authors: Stahl
authors: III Medizinische Klinik.
authors: Ulf
authors: U
authors: Panzer
authors: III Medizinische Klinik, o.steinmetz@uke.de.
authors: Oliver M
authors: OM
authors: Steinmetz
mesh_terms: D000818:Animals; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054399:Receptors, CCR6 / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: C106311:CCR6 protein, human; C498126:CCR6 protein, mouse; D054399:Receptors, CCR6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse
keywords: Acupuncture; migraine; pain