title: Histone Deacetylase 3 Is Required for T Cell Maturation.
abstract: Recent thymic emigrants are newly generated T cells that need to undergo postthymic maturation to gain functional competency and enter the long-lived naive T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. Because NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. Although thymic populations are similar in CD4-cre HDAC3 conditional knockout mice compared with wild-type mice, the peripheral numbers of CD4(+) and CD8(+) T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naive T cells are recent thymic emigrants, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 conditional knockout mice do not have a defect in intrathymic migration, thymic egress, T cell survival, or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Fan-Chi
authors.initials: FC
authors.lastname: Hsu
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Belmonte
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Constans
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Meibo W
authors.initials: MW
authors.lastname: Chen
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and.
authors.forename: Douglas C
authors.initials: DC
authors.lastname: McWilliams
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Hiebert
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905; and shapiro.virginia1@mayo.edu.
authors.forename: Virginia Smith
authors.initials: VS
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003167:Complement Activation / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D015851:Interleukin-7 / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D000099186:Histone Deacetylase 3
chemical_list: D003165:Complement System Proteins; D006655:Histone Deacetylases; D015851:Interleukin-7; D048069:Tumor Necrosis Factors; D000099186:Histone Deacetylase 3