Reciprocal control of G 1-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision

Takehito Sato, Tomoki Chiba, Shin Ichiro Ohno, Chiharu Sato, Tatsuya Sugoh, Keiko Miyashita, Hisako Akatsuka, Katsuto Hozumi, Yoshinori Okada, Yumi Iida, Akira Akatsuka, Yasutoshi Agata, Marin Chiba, Kazuyoshi Kohu, Masanobu Satake, Hideyuki Tanabe, Hideyuki Saya, Sonoko Habu

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3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)4426-4436
Number of pages11
JournalJournal of Immunology
Volume189
Issue number9
DOIs
Publication statusPublished - 2012 Nov 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Sato, T., Chiba, T., Ohno, S. I., Sato, C., Sugoh, T., Miyashita, K., Akatsuka, H., Hozumi, K., Okada, Y., Iida, Y., Akatsuka, A., Agata, Y., Chiba, M., Kohu, K., Satake, M., Tanabe, H., Saya, H., & Habu, S. (2012). Reciprocal control of G 1-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision. Journal of Immunology, 189(9), 4426-4436. https://doi.org/10.4049/jimmunol.1102748