Tle corepressors are differentially partitioned to instruct CD8⁺ T cell lineage choice and identity

Tle/Groucho proteins are transcriptional corepressors interacting with Tcf/Lef and Runx transcription factors, but their physiological roles in T cell development remain unknown. Conditional targeting of Tle1, Tle3 and Tle4 revealed gene dose–dependent requirements for Tle proteins in CD8⁺ lineage cells. Upon ablating all three Tle proteins, generation of CD8⁺ T cells was greatly diminished, largely owing to redirection of MHC-I–selected thymocytes to CD4⁺ lineage; the remaining CD8-positive T cells showed aberrant up-regulation of CD4⁺ lineage-associated genes including Cd4, Thpok, St8sia6, and Foxp3. Mechanistically, Tle3 bound to Runx-occupied Thpok silencer, in post-selection double-positive thymocytes to prevent excessive ThPOK induction and in mature CD8⁺ T cells to silence Thpok expression. Tle3 also bound to Tcf1-occupied sites in a few CD4⁺ lineage-associated genes, including Cd4 silencer and St8sia6 introns, to repress their expression in mature CD8⁺ T cells. These findings indicate that Tle corepressors are differentially partitioned to Runx and Tcf/Lef complexes to instruct CD8⁺ lineage choice and cooperatively establish CD8⁺ T cell identity, respectively.