Stat3 programs Th17-specific regulatory T cells to control GN

J Am Soc Nephrol. 2014 Jun;25(6):1291-302. doi: 10.1681/ASN.2013080904. Epub 2014 Feb 7.


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.

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Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / immunology*
  • Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / pathology
  • Cell Movement / immunology
  • Disease Models, Animal
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • Humans
  • Kidney / immunology
  • Kidney / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, CCR6 / immunology
  • Receptors, CCR6 / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / immunology*
  • STAT3 Transcription Factor / metabolism
  • Spleen / cytology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / pathology


  • CCR6 protein, human
  • CCR6 protein, mouse
  • Receptors, CCR6
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse