HDAC3 Is Required for the Downregulation of RORγt during Thymocyte Positive Selection

• Published in: The Journal of immunology (1950) 2016-07, Vol.197 (2), p.541-554
• Main Authors: Philips, Rachael L, Chen, Meibo W, McWilliams, Douglas C, Belmonte, Paul J, Constans, Megan M, Shapiro, Virginia Smith
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - immunology; Chromatin Immunoprecipitation; Down-Regulation; Flow Cytometry; Gene Expression Regulation - immunology; Histone Deacetylases - immunology; Histone Deacetylases - metabolism; Mice; Mice, Knockout; Mice, Transgenic; Nuclear Receptor Subfamily 1, Group F, Member 3 - immunology; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Thymocytes - cytology; Thymocytes - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1502529

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) γt 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.