HDAC3 is required for the downregulation of RORγt during thymocyte positive selection

Rachael L. Philips, Meibo W. Chen, Douglas C. McWilliams, Paul J. Belmonte, Megan M. Constans, Virginia M Shapiro

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

To generate functional peripheral T cells, proper gene regulation during T cell development is critical. In this study, we found that histone deacetylase (HDAC) 3 is required for T cell development. T cell development in CD2-icre HDAC3 conditional knockout (cKO) mice (HDAC3-cKO) was blocked at positive selection, resulting in few CD4 and CD8 T cells, and it could not be rescued by a TCR transgene. These single-positive thymocytes failed to upregulate Bcl-2, leading to increased apoptosis. HDAC3-cKO mice failed to downregulate retinoic acid-related orphan receptor (ROR) gt during positive selection, similar to the block in positive selection in RORγt transgenic mice. In the absence of HDAC3, the RORC promoter was hyperacetylated. In the periphery, the few CD4 T cells present were skewed toward RORγt+ IL-17-producing Th17 cells, leading to inflammatory bowel disease. Positive selection of CD8 single-positive thymocytes was restored in RORγt-KO Bcl-xL transgenic HDAC3-cKO mice, demonstrating that HDAC3 is required at positive selection to downregulate RORγt.

Original languageEnglish (US)
Pages (from-to)541-554
Number of pages14
JournalJournal of Immunology
Volume197
Issue number2
DOIs
StatePublished - Jul 15 2016

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Thymocytes
Down-Regulation
T-Lymphocytes
Knockout Mice
Th17 Cells
Interleukin-17
Tretinoin
Transgenes
Inflammatory Bowel Diseases
Transgenic Mice
Up-Regulation
Apoptosis
Genes

ASJC Scopus subject areas

  • Immunology

Cite this

Philips, R. L., Chen, M. W., McWilliams, D. C., Belmonte, P. J., Constans, M. M., & Shapiro, V. M. (2016). HDAC3 is required for the downregulation of RORγt during thymocyte positive selection. Journal of Immunology, 197(2), 541-554. https://doi.org/10.4049/jimmunol.1502529

HDAC3 is required for the downregulation of RORγt during thymocyte positive selection. / Philips, Rachael L.; Chen, Meibo W.; McWilliams, Douglas C.; Belmonte, Paul J.; Constans, Megan M.; Shapiro, Virginia M.

In: Journal of Immunology, Vol. 197, No. 2, 15.07.2016, p. 541-554.

Research output: Contribution to journalArticle

Philips, RL, Chen, MW, McWilliams, DC, Belmonte, PJ, Constans, MM & Shapiro, VM 2016, 'HDAC3 is required for the downregulation of RORγt during thymocyte positive selection', Journal of Immunology, vol. 197, no. 2, pp. 541-554. https://doi.org/10.4049/jimmunol.1502529
Philips, Rachael L. ; Chen, Meibo W. ; McWilliams, Douglas C. ; Belmonte, Paul J. ; Constans, Megan M. ; Shapiro, Virginia M. / HDAC3 is required for the downregulation of RORγt during thymocyte positive selection. In: Journal of Immunology. 2016 ; Vol. 197, No. 2. pp. 541-554.
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