title: Histone deacetylase 7 regulates cell survival and TCR signaling in CD4/CD8 double-positive thymocytes.
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.
authors.affiliation: Gladstone Institute of Virology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Herbert G
authors.initials: HG
authors.lastname: Kasler
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Denis
authors.initials: D
authors.lastname: Mottet
authors.forename: Hyung W
authors.initials: HW
authors.lastname: Lim
authors.forename: Amy M
authors.initials: AM
authors.lastname: Collins
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Eric
authors.initials: E
authors.lastname: Verdin
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D015704:CD4 Antigens / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D005260:Female; D020869:Gene Expression Profiling; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D011948:Receptors, Antigen, T-Cell; C089212:protein kinase D; D011493:Protein Kinase C; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases