Histone Deacetylase 3 Is Required for Efficient T Cell Development.
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.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Kristy R
KR
Stengel
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Yue
Y
Zhao
Department of Biology, The University of the South: Sewanee, Sewanee, Tennessee, USA.
Nicholas J
NJ
Klus
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Jonathan F
JF
Kaiser
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Laura E
LE
Gordy
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Veterans Administration Tennessee Valley Healthcare System, Nashville, Tennessee, USA.
Sebastian
S
Joyce
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA scott.hiebert@vanderbilt.edu arsummer@sewanee.edu.
Scott W
SW
Hiebert
Department of Biology, The University of the South: Sewanee, Sewanee, Tennessee, USA scott.hiebert@vanderbilt.edu arsummer@sewanee.edu.
Alyssa R
AR
Summers
D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D016827:CD8 Antigens / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics; D000099186:Histone Deacetylase 3
D015704:CD4 Antigens; D016827:CD8 Antigens; D006655:Histone Deacetylases; D019253:Proto-Oncogene Proteins c-bcl-2; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051020:bcl-X Protein; D000099186:Histone Deacetylase 3; C494812:Bcl2l1 protein, mouse