Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1

Gerd Meyer Zu Horste; Dariusz Przybylski; Markus A Schramm; Chao Wang; Alexandra Schnell; Youjin Lee; Raymond Sobel; Aviv Regev; Vijay K Kuchroo

doi:10.1016/j.immuni.2018.03.008

Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1

Immunity. 2018 Mar 20;48(3):556-569.e7. doi: 10.1016/j.immuni.2018.03.008.

Authors

Gerd Meyer Zu Horste¹, Dariusz Przybylski², Markus A Schramm³, Chao Wang³, Alexandra Schnell³, Youjin Lee³, Raymond Sobel⁴, Aviv Regev⁵, Vijay K Kuchroo⁶

Affiliations

¹ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, University Hospital Münster, Münster, Germany.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: aregev@broadinstitute.org.
⁶ Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: vkuchroo@evergrande.hms.harvard.edu.

PMID: 29562202
DOI: 10.1016/j.immuni.2018.03.008

Abstract

The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin-17 (IL-17)-producing T helper 17 (Th17) cells. Here, we demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T-cell- and Th17-cell-specific deletion of Fas were protected from induced autoimmunity, and Th17 cell differentiation and stability were impaired. Fas-deficient Th17 cells instead developed a Th1-cell-like transcriptional profile, which a new algorithm predicted to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1, and Fas deficiency enhanced IL-6-induced STAT1 activation and nuclear translocation, whereas deficiency of STAT1 reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of opposing STAT1 and STAT3 to have a direct impact on autoimmunity.

Keywords: CD95; EAE; Fas; STAT1; STAT3; Th1 cells; Th17 cells; apoptosis; autoimmunity; death receptor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / immunology
Biomarkers
Caspases / metabolism
Cell Differentiation / immunology*
Gene Expression Profiling
Gene Knockout Techniques
Lymphocyte Activation
Mice
Phenotype
Phosphorylation
Protein Binding
Protein Transport
STAT1 Transcription Factor / metabolism*
STAT3 Transcription Factor / metabolism
Th1 Cells / immunology*
Th1 Cells / metabolism*
Th17 Cells / cytology
Th17 Cells / immunology*
Th17 Cells / metabolism*
Transcriptome
fas Receptor / genetics
fas Receptor / metabolism*

Substances

Biomarkers
STAT1 Transcription Factor
STAT3 Transcription Factor
fas Receptor
Caspases

Abstract

Publication types

MeSH terms

Substances

Grants and funding