title: Reciprocal control of G1-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision.
abstract: After receiving a TCR-mediated differentiation signal, CD4 and CD8 double-positive thymocytes diverge into CD4 or CD8 single-positive T cells, for which Th-POK and Runx3 have been identified as pivotal transcription factors, respectively. The cross-antagonistic regulation of Th-POK and Runx3 seems to be essential for CD4/8 thymocyte lineage commitment. However, the process for determining which pivotal factor acts dominantly has not been established. To explore the determining process, we used an in vitro culture system in which CD4 or CD8 single-positive cells are selectively induced from CD4/8 double-positive cells. Surprisingly, we found that control of G(1) cell cycle phase progression is critical for the determination. In the CD4 pathway, sustained TCR signal, as well as Th-POK, induces G(1)-phase extension and represses CD8 expression in a G(1) extension-dependent manner. In the CD8 pathway, after receiving a transient TCR signal, the IL-7R signal, as well as Runx3, antagonizes TCR signal-mediated G(1) extension and CD8 repression. Importantly, forced G(1) extension cancels the functions of Runx3 to repress Th-POK and CD4 and to reactivate CD8. In contrast, it is suggested that forced G(1) progression inhibits Th-POK function to repress CD8. Collectively, Th-POK and Runx3 are reciprocally involved in the control of G(1)-phase progression, on which they exert their functions dependently. These findings may provide novel insight into how CD4/CD8 cell lineages are determined by Th-POK and Runx3.
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Kanagawa 259-1193, Japan. takehito@is.icc.u-tokai.ac.jp
authors.forename: Takehito
authors.initials: T
authors.lastname: Sato
authors.forename: Tomoki
authors.initials: T
authors.lastname: Chiba
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Ohno
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sato
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Sugoh
authors.forename: Keiko
authors.initials: K
authors.lastname: Miyashita
authors.forename: Hisako
authors.initials: H
authors.lastname: Akatsuka
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Okada
authors.forename: Yumi
authors.initials: Y
authors.lastname: Iida
authors.forename: Akira
authors.initials: A
authors.lastname: Akatsuka
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Agata
authors.forename: Marin
authors.initials: M
authors.lastname: Chiba
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kohu
authors.forename: Masanobu
authors.initials: M
authors.lastname: Satake
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tanabe
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.forename: Sonoko
authors.initials: S
authors.lastname: Habu
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology*; D050677:Core Binding Factor Alpha 3 Subunit / Q000502:physiology*; D016193:G1 Phase / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D050677:Core Binding Factor Alpha 3 Subunit; D014157:Transcription Factors; C493730:Runx3 protein, mouse; C497211:Zbtb7b protein, mouse