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

Rachael Laura Philips, Jeong Heon Lee, Krutika Gaonkar, Pritha Chanana, Ji Young Chung, Sinibaldo R. Romero Arocha, Aaron Schwab, Tamas Ordog, Virginia M Shapiro

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournaleLife
Volume8
DOIs
StatePublished - Jan 18 2019

Fingerprint

Thymocytes
Genes
T-cells
T-Lymphocytes
Acetylation
Immune system
Cellular Structures
histone deacetylase 3
Histones
Immune System
RNA
Cytokines
Kinetics

Keywords

  • HDAC3
  • immunology
  • inflammation
  • lineage commitment
  • mouse
  • T cell development

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

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 M.

In: eLife, Vol. 8, 18.01.2019.

Research output: Contribution to journalArticle

Philips, Rachael Laura ; Lee, Jeong Heon ; Gaonkar, Krutika ; Chanana, Pritha ; Chung, Ji Young ; Romero Arocha, Sinibaldo R. ; Schwab, Aaron ; Ordog, Tamas ; Shapiro, Virginia M. / HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment. In: eLife. 2019 ; Vol. 8.
@article{8b432d2d53e4427eb35f3925b12a12e5,
title = "HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment",
abstract = "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.",
keywords = "HDAC3, immunology, inflammation, lineage commitment, mouse, T cell development",
author = "Philips, {Rachael Laura} and Lee, {Jeong Heon} and Krutika Gaonkar and Pritha Chanana and Chung, {Ji Young} and {Romero Arocha}, {Sinibaldo R.} and Aaron Schwab and Tamas Ordog and Shapiro, {Virginia M}",
year = "2019",
month = "1",
day = "18",
doi = "10.7554/eLife.43821",
language = "English (US)",
volume = "8",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",

}

TY - JOUR

T1 - HDAC3 restrains CD8-lineage genes to maintain a bi-potential state in CD4+CD8+ thymocytes for CD4-lineage commitment

AU - Philips, Rachael Laura

AU - Lee, Jeong Heon

AU - Gaonkar, Krutika

AU - Chanana, Pritha

AU - Chung, Ji Young

AU - Romero Arocha, Sinibaldo R.

AU - Schwab, Aaron

AU - Ordog, Tamas

AU - Shapiro, Virginia M

PY - 2019/1/18

Y1 - 2019/1/18

N2 - 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.

AB - 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.

KW - HDAC3

KW - immunology

KW - inflammation

KW - lineage commitment

KW - mouse

KW - T cell development

UR - http://www.scopus.com/inward/record.url?scp=85060142676&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060142676&partnerID=8YFLogxK

U2 - 10.7554/eLife.43821

DO - 10.7554/eLife.43821

M3 - Article

C2 - 30657451

AN - SCOPUS:85060142676

VL - 8

JO - eLife

JF - eLife

SN - 2050-084X

ER -