Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape

Laurent Chorro; Masako Suzuki; Shu Shien Chin; Tere M Williams; Erik L Snapp; Livia Odagiu; Nathalie Labrecque; Grégoire Lauvau

doi:10.1038/s41467-018-07806-6

Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape

Nat Commun. 2018 Dec 18;9(1):5368. doi: 10.1038/s41467-018-07806-6.

Authors

Laurent Chorro¹, Masako Suzuki², Shu Shien Chin¹, Tere M Williams¹, Erik L Snapp^{3

4}, Livia Odagiu⁵, Nathalie Labrecque⁵, Grégoire Lauvau⁶

Affiliations

¹ Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
² Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
³ Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
⁴ Janelia Research Campus of the Howard Hughes Medical Institute, Ashburn, VA, 20147, USA.
⁵ Maisonneuve-Rosemont Hospital Research Center and Department of Medicine and Microbiology, Immunology and Infectiology, University of Montreal, 5345 Boulevard de l'Assomption, Montréal, QC, H1T 4B3, Canada.
⁶ Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. [email protected].

Abstract

Foxp3⁺CD4⁺ regulatory T (T_reg) cells are essential for preventing fatal autoimmunity and safeguard immune homeostasis in vivo. While expression of the transcription factor Foxp3 and IL-2 signals are both required for the development and function of T_reg cells, the commitment to the T_reg cell lineage occurs during thymic selection upon T cell receptor (TCR) triggering, and precedes the expression of Foxp3. Whether signals beside TCR contribute to establish T_reg cell epigenetic and functional identity is still unknown. Here, using a mouse model with reduced IL-2 signaling, we show that IL-2 regulates the positioning of the pioneer factor SATB1 in CD4⁺ thymocytes and controls genome wide chromatin accessibility of thymic-derived T_reg cells. We also show that T_reg cells receiving only low IL-2 signals can suppress endogenous but not WT autoreactive T cell responses in vitro and in vivo. Our findings have broad implications for potential therapeutic strategies to reprogram T_reg cells in vivo.

Publication types

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

MeSH terms

Animals
Autoimmunity / genetics
Cell Differentiation / immunology
Cellular Reprogramming / genetics*
Cellular Reprogramming / immunology
Disease Models, Animal
Epigenesis, Genetic / immunology*
Female
Forkhead Transcription Factors / immunology
Forkhead Transcription Factors / metabolism
HEK293 Cells
Humans
Interleukin-2 / immunology
Interleukin-2 / metabolism*
Interleukin-2 Receptor alpha Subunit / genetics
Interleukin-2 Receptor alpha Subunit / immunology
Interleukin-2 Receptor alpha Subunit / metabolism
Listeriosis / immunology
Listeriosis / microbiology
Male
Matrix Attachment Region Binding Proteins / genetics
Matrix Attachment Region Binding Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Signal Transduction / genetics
Signal Transduction / immunology
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Thymocytes / immunology
Thymocytes / metabolism
Thymocytes / physiology
Thymus Gland / cytology

Substances

Forkhead Transcription Factors
Foxp3 protein, mouse
Il2ra protein, mouse
Interleukin-2
Interleukin-2 Receptor alpha Subunit
Matrix Attachment Region Binding Proteins
Satb1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding