title: RORγt(+)Foxp3(+) Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN.
abstract: Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORγt have been identified (biTregs). It is unclear whether RORγt(+)Foxp3(+) biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN. Induction of NTN resulted in rapid renal and systemic expansion of biTregs. Notably, analyses of the biTreg expression profile revealed production of both anti-inflammatory (IL-10, IL-35) and proinflammatory (IL-17) cytokines. Additionally, biTregs expressed a signature of surface molecules and transcription factors distinct from those of Th17 cells and conventional Tregs (cTregs), and biTregs were identified in Treg17-deficient mice. Finally, fate reporter and cell transfer studies confirmed that biTregs are not Treg/Th17 transdifferentiating cells. Therapeutic transfer of biTregs suppressed the development of nephritis to an extent similar to that observed with transferred cTregs, but in vitro studies indicated different mechanisms of immunosuppression for biTregs and cTregs. Intriguingely, as predicted from their cytokine profile, endogenous biTregs displayed additional proinflammatory functions in NTN that were abrogated by cell-specific deletion of RORγt. In summary, we provide evidence that RORγt(+)Foxp3(+) biTregs are a novel and independent bifunctional regulatory T cell lineage distinct from cTregs, Treg17 cells, and Th17 cells. Furthermore, biTregs appear to contribute to crescentic GN and hence may be novel therapeutic targets.
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Malte A
authors.initials: MA
authors.lastname: Kluger
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Matthias C
authors.initials: MC
authors.lastname: Meyer
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Anna
authors.initials: A
authors.lastname: Nosko
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Boeren
authors.initials: B
authors.lastname: Goerke
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Luig
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wegscheid
authors.affiliation: Institute of Experimental Immunology and Hepatology, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Gisa
authors.initials: G
authors.lastname: Tiegs
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.affiliation: III. Medical Clinic, University Hospital Eppendorf, Hamburg, Germany; and.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Steinmetz
mesh_terms: D000818:Animals; D019070:Cell Lineage; D051858:Forkhead Transcription Factors / Q000502:physiology*; D005921:Glomerulonephritis / Q000209:etiology*; D008297:Male; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
keywords: T cells; glomerulonephritis; immunology and pathology