Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes

Herbert G. Kasler, Bryan D. Young, Denis Mottet, Hyung W. Lim, Amy M. Collins, Eric N. Olson, Eric Verdin

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

CD4/CD8 double-positive thymocytes express the transcriptional repressor histone deacetylase (HDAC)7, a class IIa HDAC that is exported from the cell nucleus after TCR engagement. Through signal-dependent nuclear export, class IIa HDACs such as HDAC7 mediate signal-dependent changes in gene expression that are important to developmental fate decisions in multiple tissues. We report that HDAC7 is exported from the cell nucleus during positive selection in mouse thymocytes and that it regulates genes mediating the coupling between TCR engagement and downstream events that determine cell survival. Thymocytes lacking HDAC7 are inefficiently positively selected due to a severely shortened lifespan and exhibit a truncated repertoire of TCR Jα segments. The expression of multiple important mediators and modulators of the response to TCR engagement is altered in HDAC7-deficient thymocytes, resulting in increased tonic MAPK activity that contributes to the observed loss of viability. Remarkably, the activity of protein kinase D, the kinase that mediates nuclear export of HDAC7 in response to TCR signaling, is also increased in HDAC7-deficient thymocytes, suggesting that HDAC7 nuclear export governs a self-sustaining autoexcitatory loop. These experiments add to the understanding of the life/death decision in thymic T cell development, define a novel function for class IIa HDACs, and point to a novel feed-forward mechanism whereby these molecules regulate their own state and mediate stable developmental transitions.

Original languageEnglish (US)
Pages (from-to)4782-4793
Number of pages12
JournalJournal of Immunology
Volume186
Issue number8
DOIs
StatePublished - Apr 15 2011

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Histone Deacetylases
Thymocytes
Cell Survival
Cell Nucleus Active Transport
Cell Nucleus
Nuclear Export Signals
Phosphotransferases
T-Lymphocytes
Gene Expression
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. / Kasler, Herbert G.; Young, Bryan D.; Mottet, Denis; Lim, Hyung W.; Collins, Amy M.; Olson, Eric N.; Verdin, Eric.

In: Journal of Immunology, Vol. 186, No. 8, 15.04.2011, p. 4782-4793.

Research output: Contribution to journalArticle

Kasler, Herbert G. ; Young, Bryan D. ; Mottet, Denis ; Lim, Hyung W. ; Collins, Amy M. ; Olson, Eric N. ; Verdin, Eric. / Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes. In: Journal of Immunology. 2011 ; Vol. 186, No. 8. pp. 4782-4793.
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