Histone Deacetylase 3 Is Required for Efficient T Cell Development

Abstract

Hdac3 is a key target for Hdac inhibitors that are efficacious in cutaneous T cell lymphoma. Moreover, the regulation of chromatin structure is critical as thymocytes transition from an immature cell with open chromatin to a mature T cell with tightly condensed chromatin. To define the phenotypes controlled by Hdac3 during T cell development, we conditionally deleted Hdac3 using the Lck-Cre transgene. This strategy inactivated Hdac3 in the double-negative stages of thymocyte development and caused a significant impairment at the CD8 immature single-positive (ISP) stage and the CD4/CD8 double-positive stage, with few mature CD4⁺ or CD8⁺ single-positive cells being produced. When Hdac3^−/− mice were crossed with Bcl-xL-, Bcl2-, or TCRβ-expressing transgenic mice, a modest level of complementation was found. However, when the null mice were crossed with mice expressing a fully rearranged T cell receptor αβ transgene, normal levels of CD4 single-positive cells were produced. Thus, Hdac3 is required for the efficient transit from double-negative stage 4 through positive selection.

ACKNOWLEDGMENTS

We thank all the members of the S. W. Hiebert lab for helpful discussions, reagents, and advice. We thank the Vanderbilt Cell Imaging, Translational Pathology, Flow Cytometry, and Vantage Shared Resources for services and support.

This work was supported by the T. J. Martell Foundation, the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation, and National Institutes of Health grants (RO1-CA109355, RO1-CA164605 and R01-CA64140 to S.W.H.; R01-AI061721 to S.J.), and core services were performed through a Vanderbilt digestive disease research grant (NIDDK P30DK58404) and a Vanderbilt-Ingram Cancer Center support grant (NCI P30CA68485). A.R.S. was supported by a fellowship from the NIH (5F32HL090259), K.R.S. was supported by grant 5 T32 CA009582-26 from the NCI and a postdoctoral fellowship (PF-13-303-01-DMC) from the American Cancer Society, and L.E.G. was supported by training grant HL069765. The project described was also supported by the National Center for Research Resources (grant UL1 RR024975-01) and is now supported by the National Center for Advancing Translational Sciences (grant 2 UL1 TR000445-06).

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We declare that no conflict of interest exists.