Differential requirements for Runx proteins in CD4 repression and epigenetic silencing during T lymphocyte development.
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.
Taniuchi
Ichiro
I
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
Osato
Motomi
M
Egawa
Takeshi
T
Sunshine
Mary Jean
MJ
Bae
Suk Chul
SC
Komori
Toshihisa
T
Ito
Yoshiaki
Y
Littman
Dan R
DR
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*
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