title: Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development.
abstract: T lymphocytes differentiate in discrete stages within the thymus. Immature thymocytes lacking CD4 and CD8 coreceptors differentiate into double-positive cells (CD4(+)CD8(+)), which are selected to become either CD4(+)CD8(-)helper cells or CD4(-)CD8(+) cytotoxic cells. A stage-specific transcriptional silencer regulates expression of CD4 in both immature and CD4(-)CD8(+) thymocytes. We show here that binding sites for Runt domain transcription factors are essential for CD4 silencer function at both stages, and that different Runx family members are required to fulfill unique functions at each stage. Runx1 is required for active repression in CD4(-)CD8(-) thymocytes whereas Runx3 is required for establishing epigenetic silencing in cytotoxic lineage thymocytes. Runx3-deficient cytotoxic T cells, but not helper cells, have defective responses to antigen, suggesting that Runx proteins have critical functions in lineage specification and homeostasis of CD8-lineage T lymphocytes.
authors.affiliation: Howard Hughes Medical Institute, Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA. taniuchi@bioreg.kyushu-u.ac.jp
authors.forename: Ichiro
authors.initials: I
authors.lastname: Taniuchi
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.forename: Takeshi
authors.initials: T
authors.lastname: Egawa
authors.forename: Mary Jean
authors.initials: MJ
authors.lastname: Sunshine
authors.forename: Suk Chul
authors.initials: SC
authors.lastname: Bae
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Komori
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ito
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015704:CD4 Antigens / Q000235:genetics*; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D017354:Point Mutation; D012097:Repressor Proteins / Q000502:physiology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D014157:Transcription Factors / Q000172:deficiency / Q000502:physiology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C493729:Runx3 protein, human; C493730:Runx3 protein, mouse; D014157:Transcription Factors