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A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells.
Van Gool, Frédéric; Nguyen, Michelle L T; Mumbach, Maxwell R; Satpathy, Ansuman T; Rosenthal, Wendy L; Giacometti, Simone; Le, Duy T; Liu, Weihong; Brusko, Todd M; Anderson, Mark S; Rudensky, Alexander Y; Marson, Alexander; Chang, Howard Y; Bluestone, Jeffrey A.
Afiliación
  • Van Gool F; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Nguyen MLT; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Mumbach MR; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Satpathy AT; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Rosenthal WL; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Giacometti S; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Le DT; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Liu W; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Brusko TM; Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
  • Anderson MS; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Rudensky AY; Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Marson A; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Chang HY; Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
  • Bluestone JA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeff.bluestone@ucsf.edu.
Immunity ; 50(2): 362-377.e6, 2019 02 19.
Article en En | MEDLINE | ID: mdl-30709738
ABSTRACT
Regulatory T (Treg) cells maintain immune tolerance through the master transcription factor forkhead box P3 (FOXP3), which is crucial for Treg cell function and homeostasis. We identified an IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) syndrome patient with a FOXP3 mutation in the domain swap interface of the protein. Recapitulation of this Foxp3 variant in mice led to the development of an autoimmune syndrome consistent with an unrestrained T helper type 2 (Th2) immune response. Genomic analysis of Treg cells by RNA-sequencing, Foxp3 chromatin immunoprecipitation followed by high-throughput DNA sequencing (ChIP-sequencing), and H3K27ac-HiChIP revealed a specific de-repression of the Th2 transcriptional program leading to the generation of Th2-like Treg cells that were unable to suppress extrinsic Th2 cells. Th2-like Treg cells showed increased intra-chromosomal interactions in the Th2 locus, leading to type 2 cytokine production. These findings identify a direct role for Foxp3 in suppressing Th2-like Treg cells and implicate additional pathways that could be targeted to restrain Th2 trans-differentiated Treg cells.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T Reguladores / Células Th2 / Factores de Transcripción Forkhead / Mutación Tipo de estudio: Prognostic_studies Límite: Animals / Child / Humans / Male Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Linfocitos T Reguladores / Células Th2 / Factores de Transcripción Forkhead / Mutación Tipo de estudio: Prognostic_studies Límite: Animals / Child / Humans / Male Idioma: En Revista: Immunity Asunto de la revista: ALERGIA E IMUNOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos