Thpok-independent repression of Runx3 by Gata3 during CD4+ T-cell differentiation in the thymus.

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. [ABSTRACT FROM AUTHOR]