Reciprocal control of G1-phase progression is required for Th-POK/Runx3-mediated CD4/8 thymocyte cell fate decision.

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.

IκBL, a novel member of the nuclear IκB family, inhibits inflammatory cytokine expression.

We previously reported that IκBL prevents experimental autoimmune arthritis. The molecular mechanism, however, still remains unclear. In contrast to four splicing-isoforms of IκBL in human, two isoforms were identified in mouse. The major isoform IκBL-α(S) suppressed LPS-induced NF-κB activation and transcription of TNFα and IL-6, but not IL-1ß. The suppressive activity required the nuclear localization signal and the ankyrin repeat domain of IκBL. IκBL did not affect the nuclear translocation of the NF-κB dimer. These findings point to IκBL as being a novel member of the nuclear IκB family, which functions in the nucleus and controls various inflammatory responses including autoimmune arthritis.