The production of αβ T cells in the thymus involves multiple steps. First, progenitor cells termed ‘thymocytes’ that do not express CD4 and CD8 differentiate to become CD4+CD8+ double-positive (DP) cells. These cells then mature to give rise to CD4 and CD4 single-positive (SP) populations. The CD4/CD8 lineage decision is known to be influenced by multiple factors, including Tcra locus rearrangement, TCR signalling and positive selection. Now, Tessa Crompton and co-workers report that this process involves the pioneer transcription factors Foxa1 and Foxa2. They first show that both Foxa1 and Foxa2 are expressed in thymocytes and are required for T-cell development. Specifically, conditional deletion of Foxa1 and Foxa2 from developing DP thymocytes leads to reduced numbers of SP cells and reduced SP cell maturation. The researchers further show that Foxa1/2 conditional deletion causes significant changes in the expression of RNA splicing-related genes. In line with this, they identify >850 differentially used exons in Foxa1/2-deficient thymocytes. These exons occur within genes that are known to regulate T-cell development as well as within genes associated with RNA splicing. Together, these and other findings suggest that Foxa1 and Foxa2 contribute to thymocyte positive selection by regulating the splicing of genes essential for T-cell development, but that they also exert widespread control over alternative splicing.
