Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda 20892-4259, MD, USA.
Eur J Immunol. 2013 Apr;43(4):918-28. doi: 10.1002/eji.201242944. Epub 2013 Feb 12.
CD4(+) helper T cells are essential for immune responses and differentiate in the thymus from CD4(+) CD8(+) "double-positive" (DP) thymocytes. The transcription factor Runx3 inhibits CD4(+) T-cell differentiation by repressing Cd4 gene expression; accordingly, Runx3 is not expressed in DP thymocytes or developing CD4(+) T cells. The transcription factor Thpok is upregulated in CD4-differentiating thymocytes and required to repress Runx3. However, how Runx3 is controlled at early stages of CD4(+) T-cell differentiation, before the onset of Thpok expression, remains unknown. Here we show that Gata3, a transcription factor preferentially and transiently upregulated by CD4(+) T-cell precursors, represses Runx3 and binds the Runx3 locus in vivo. Accordingly, we show that high-level Gata3 expression and expression of Runx3 are mutually exclusive. Furthermore, whereas Runx3 represses Cd4, we show that Gata3 promotes Cd4 expression in Thpok-deficient thymocytes. Thus, in addition to its previously documented role in promoting CD4-lineage gene-expression, Gata3 represses CD8-lineage gene expression. These findings identify Gata3 as a critical pivot of CD4-CD8 lineage differentiation.
CD4(+) 辅助 T 细胞对于免疫反应至关重要，它们在胸腺中从 CD4(+) CD8(+) “双阳性”(DP) 胸腺细胞分化而来。转录因子 Runx3 通过抑制 Cd4 基因的表达来抑制 CD4(+) T 细胞的分化；因此，DP 胸腺细胞或正在发育的 CD4(+) T 细胞中不表达 Runx3。转录因子 Thpok 在正在分化为 CD4 的胸腺细胞中上调，并需要抑制 Runx3。然而，在 Thpok 表达之前的 CD4(+) T 细胞分化的早期阶段，Runx3 是如何被控制的仍然未知。在这里，我们表明转录因子 Gata3 在 CD4(+) T 细胞前体中优先且短暂地上调，它可以抑制 Runx3 并在体内结合 Runx3 基因座。因此，我们表明高水平的 Gata3 表达和 Runx3 表达是相互排斥的。此外，尽管 Runx3 抑制 Cd4，但我们表明 Gata3 可以促进 Thpok 缺陷型胸腺细胞中 Cd4 的表达。因此，除了其先前在促进 CD4 谱系基因表达方面的作用外，Gata3 还抑制 CD8 谱系基因表达。这些发现确定了 Gata3 是 CD4-CD8 谱系分化的关键枢纽。
