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HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment

CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are re...

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Autores principales: Philips, Rachael Laura, Lee, Jeong-Heon, Gaonkar, Krutika, Chanana, Pritha, Chung, Ji Young, Romero Arocha, Sinibaldo R, Schwab, Aaron, Ordog, Tamas, Shapiro, Virginia Smith
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338460/
https://www.ncbi.nlm.nih.gov/pubmed/30657451
http://dx.doi.org/10.7554/eLife.43821
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author Philips, Rachael Laura
Lee, Jeong-Heon
Gaonkar, Krutika
Chanana, Pritha
Chung, Ji Young
Romero Arocha, Sinibaldo R
Schwab, Aaron
Ordog, Tamas
Shapiro, Virginia Smith
author_facet Philips, Rachael Laura
Lee, Jeong-Heon
Gaonkar, Krutika
Chanana, Pritha
Chung, Ji Young
Romero Arocha, Sinibaldo R
Schwab, Aaron
Ordog, Tamas
Shapiro, Virginia Smith
author_sort Philips, Rachael Laura
collection PubMed
description CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells.
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spelling pubmed-63384602019-01-24 HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment Philips, Rachael Laura Lee, Jeong-Heon Gaonkar, Krutika Chanana, Pritha Chung, Ji Young Romero Arocha, Sinibaldo R Schwab, Aaron Ordog, Tamas Shapiro, Virginia Smith eLife Immunology and Inflammation CD4 and CD8 T cells are vital components of the immune system. We found that histone deacetylase 3 (HDAC3) is critical for the development of CD4 T cells, as HDAC3-deficient DP thymocytes generate only CD8SP thymocytes in mice. In the absence of HDAC3, MHC Class II-restricted OT-II thymocytes are redirected to the CD8 cytotoxic lineage, which occurs with accelerated kinetics. Analysis of histone acetylation and RNA-seq reveals that HDAC3-deficient DP thymocytes are biased towards the CD8 lineage prior to positive selection. Commitment to the CD4 or CD8 lineage is determined by whether persistent TCR signaling or cytokine signaling predominates, respectively. Despite elevated IL-21R/γc/STAT5 signaling in HDAC3-deficient DP thymocytes, blocking IL-21R does not restore CD4 lineage commitment. Instead, HDAC3 binds directly to CD8-lineage promoting genes. Thus, HDAC3 is required to restrain CD8-lineage genes in DP thymocytes for the generation of CD4 T cells. eLife Sciences Publications, Ltd 2019-01-18 /pmc/articles/PMC6338460/ /pubmed/30657451 http://dx.doi.org/10.7554/eLife.43821 Text en © 2019, Philips et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Immunology and Inflammation
Philips, Rachael Laura
Lee, Jeong-Heon
Gaonkar, Krutika
Chanana, Pritha
Chung, Ji Young
Romero Arocha, Sinibaldo R
Schwab, Aaron
Ordog, Tamas
Shapiro, Virginia Smith
HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment
title HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment
title_full HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment
title_fullStr HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment
title_full_unstemmed HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment
title_short HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4(+)CD8(+) thymocytes for CD4-lineage commitment
title_sort hdac3 restrains cd8-lineage genes to maintain a bi-potential state in cd4(+)cd8(+) thymocytes for cd4-lineage commitment
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338460/
https://www.ncbi.nlm.nih.gov/pubmed/30657451
http://dx.doi.org/10.7554/eLife.43821
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