title: Stable inhibitory activity of regulatory T cells requires the transcription factor Helios.
abstract: The maintenance of immune homeostasis requires regulatory T cells (T(regs)). Given their intrinsic self-reactivity, T(regs) must stably maintain a suppressive phenotype to avoid autoimmunity. We report that impaired expression of the transcription factor (TF) Helios by FoxP3(+) CD4 and Qa-1-restricted CD8 T(regs) results in defective regulatory activity and autoimmunity in mice. Helios-deficient T(regs) develop an unstable phenotype during inflammatory responses characterized by reduced FoxP3 expression and increased effector cytokine expression secondary to diminished activation of the STAT5 pathway. CD8 T(regs) also require Helios-dependent STAT5 activation for survival and to prevent terminal T cell differentiation. The definition of Helios as a key transcription factor that stabilizes T(regs) in the face of inflammatory responses provides a genetic explanation for a core property of T(regs).
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA.
authors.forename: Hye-Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Barnitz
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA.
authors.forename: Taras
authors.initials: T
authors.lastname: Kreslavsky
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Flavian D
authors.initials: FD
authors.lastname: Brown
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Howell
authors.initials: H
authors.lastname: Moffett
authors.affiliation: Bioinfo, Plantagenet, Canada.
authors.forename: Madeleine E
authors.initials: ME
authors.lastname: Lemieux
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Kaygusuz
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA.
authors.forename: Torsten
authors.initials: T
authors.lastname: Meissner
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA.
authors.forename: Tobias A W
authors.initials: TA
authors.lastname: Holderried
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France. Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
authors.forename: Susan
authors.initials: S
authors.lastname: Chan
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR 7104, Université de Strasbourg, 67404 Illkirch, France. Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Kastner
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: W Nicholas
authors.initials: WN
authors.lastname: Haining
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Department of Microbiology and Immunobiology, Division of Immunology, Harvard Medical School, Boston MA. harvey_cantor@dfci.harvard.edu.
authors.forename: Harvey
authors.initials: H
authors.lastname: Cantor
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000276:immunology; D015870:Gene Expression; D007668:Kidney / Q000276:immunology; D008099:Liver / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology; D050799:STAT5 Transcription Factor / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D050799:STAT5 Transcription Factor; D014157:Transcription Factors; C491746:Zfpn1a2 protein, mouse