The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development

Florian Renoux; Mara Stellato; Claudia Haftmann; Alexander Vogetseder; Riyun Huang; Arun Subramaniam; Mike O Becker; Przemyslaw Blyszczuk; Burkhard Becher; Jörg H W Distler; Gabriela Kania; Onur Boyman; Oliver Distler

doi:10.1016/j.celrep.2020.107826

The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development

Cell Rep. 2020 Jun 30;31(13):107826. doi: 10.1016/j.celrep.2020.107826.

Authors

Affiliations

¹ Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
² Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
³ Department of Pathology, Luzerner Kantonspital, Lucerne, Switzerland.
⁴ Sanofi, Immunology and Inflammation Research TA, Cambridge, MA 02139, USA.
⁵ Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland.
⁶ Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany.
⁷ Department of Immunology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland.
⁸ Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland. Electronic address: oliver.distler@usz.ch.

PMID: 32610127
DOI: 10.1016/j.celrep.2020.107826

Abstract

Regulatory T cells (Tregs) represent a major population in the control of immune homeostasis and autoimmunity. Here we show that Fos-like 2 (Fosl2), a TCR-induced AP1 transcription factor, represses Treg development and controls autoimmunity. Mice overexpressing Fosl2 (Fosl2^tg) indeed show a systemic inflammatory phenotype, with immune infiltrates in multiple organs. This phenotype is absent in Fosl2^tg × Rag2^-/- mice lacking T and B cells, and Fosl2 induces T cell-intrinsic reduction of Treg development that is responsible for the inflammatory phenotype. Fosl2^tg T cells can transfer inflammation, which is suppressed by the co-delivery of Tregs, while Fosl2 deficiency in T cells reduces the severity of autoimmunity in the EAE model. We find that Fosl2 could affect expression of FoxP3 and other Treg development genes. Our data highlight the importance of AP1 transcription factors, in particular Fosl2, during T cell development to determine Treg differentiation and control autoimmunity.

Keywords: FoxP3; T cells; autoimmunity; immunology; inflammation; mouse models; regulatory T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity*
Bone Marrow / pathology
DNA-Binding Proteins / metabolism
Encephalomyelitis, Autoimmune, Experimental / immunology
Encephalomyelitis, Autoimmune, Experimental / pathology
Forkhead Transcription Factors / metabolism
Fos-Related Antigen-2 / metabolism*
Gene Deletion
Inflammation / immunology*
Inflammation / pathology*
Mice, Inbred C57BL
Phenotype
Receptors, Antigen, T-Cell / metabolism
T-Lymphocytes, Regulatory / immunology*
Transcription Factor AP-1 / metabolism*

Substances

DNA-Binding Proteins
Forkhead Transcription Factors
Fos-Related Antigen-2
Fosl2 protein, mouse
Foxp3 protein, mouse
Rag2 protein, mouse
Receptors, Antigen, T-Cell
Transcription Factor AP-1