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
Affiliations
Florian Renoux
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
Mara Stellato
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
Claudia Haftmann
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Alexander Vogetseder
Department of Pathology, Luzerner Kantonspital, Lucerne, Switzerland
Riyun Huang
Sanofi, Immunology and Inflammation Research TA, Cambridge, MA 02139, USA
Arun Subramaniam
Sanofi, Immunology and Inflammation Research TA, Cambridge, MA 02139, USA
Mike O. Becker
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
Przemyslaw Blyszczuk
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland; Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland
Burkhard Becher
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
Jörg H.W. Distler
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Erlangen, Germany
Gabriela Kania
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland
Onur Boyman
Department of Immunology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland
Oliver Distler
Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland; Corresponding author
Summary: 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 (Fosl2tg) indeed show a systemic inflammatory phenotype, with immune infiltrates in multiple organs. This phenotype is absent in Fosl2tg × Rag2−/− mice lacking T and B cells, and Fosl2 induces T cell-intrinsic reduction of Treg development that is responsible for the inflammatory phenotype. Fosl2tg 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.
