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

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

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Article number	5368
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-07806-6
State	Published - Dec 1 2018
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-07806-6

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@article{a735295a2dc646f0b36a760d0c381cc0,

title = "Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape",

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.",

author = "Laurent Chorro and Masako Suzuki and Chin, {Shu Shien} and Williams, {Tere M.} and Snapp, {Erik L.} and Livia Odagiu and Nathalie Labrecque and Gr{\'e}goire Lauvau",

note = "Funding Information: H2-Kb/OVA257-264and H2-Kb/gB498-505 tetramers were obtained from the NIH Tetramer Facility. We are grateful to M. Levy (Einstein) for privileged access to the FACS Aria III and thank the AECOM FACS and genomic core facilities. We thank the Lauvau laboratory members and S. Soudja for critical comments, and JF Daudelin for characterizing the transient CD25 transfectants. This work was funded by the National Institute of Health Grants (NIH) AI103338, Hirschl Caulier Award to G.L.; the Canadian Institutes of Health Research Grants PJT-149023 and PJT-152988 to N.L. L.C. received fellowships from ARC, Fondation Bettencourt-Schuller, and the American Association of Immunology (AAI). T.M.W. and S.S.C. were supported by NIH training Grant T32A170117. L.O. received a studentship from the Fonds de recherche du Qu{\'e}bec-Sant{\'e}. Core resources for FACS were supported by the Einstein Cancer Center (NCI cancer center support grant 2P30CA013330). Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

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doi = "10.1038/s41467-018-07806-6",

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AU - Chorro, Laurent

AU - Suzuki, Masako

AU - Chin, Shu Shien

AU - Williams, Tere M.

AU - Snapp, Erik L.

AU - Odagiu, Livia

AU - Labrecque, Nathalie

AU - Lauvau, Grégoire

N1 - Funding Information: H2-Kb/OVA257-264and H2-Kb/gB498-505 tetramers were obtained from the NIH Tetramer Facility. We are grateful to M. Levy (Einstein) for privileged access to the FACS Aria III and thank the AECOM FACS and genomic core facilities. We thank the Lauvau laboratory members and S. Soudja for critical comments, and JF Daudelin for characterizing the transient CD25 transfectants. This work was funded by the National Institute of Health Grants (NIH) AI103338, Hirschl Caulier Award to G.L.; the Canadian Institutes of Health Research Grants PJT-149023 and PJT-152988 to N.L. L.C. received fellowships from ARC, Fondation Bettencourt-Schuller, and the American Association of Immunology (AAI). T.M.W. and S.S.C. were supported by NIH training Grant T32A170117. L.O. received a studentship from the Fonds de recherche du Québec-Santé. Core resources for FACS were supported by the Einstein Cancer Center (NCI cancer center support grant 2P30CA013330). Publisher Copyright: © 2018, The Author(s).

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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Interleukin 2 modulates thymic-derived regulatory T cell epigenetic landscape

Abstract

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