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Immunity. 2019 Feb 19;50(2):362-377.e6. doi: 10.1016/j.immuni.2018.12.016. Epub 2019 Jan 29.

A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells.

Author information

1
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.
2
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
3
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
5
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
6
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.
7
Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
8
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.

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.

KEYWORDS:

Foxp3; GATA3; IPEX; Th2-like Treg; autoimmunity; regulatory T cells

PMID:
30709738
PMCID:
PMC6476426
DOI:
10.1016/j.immuni.2018.12.016
[Indexed for MEDLINE]
Free PMC Article

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