Mouse CD4⁺CD8⁺ double-positive (DP) thymocytes differentiate into CD4⁺ helper-lineage cells upon expression of the transcription factor Th-POK but commit to the CD8⁺ cytotoxic lineage in its absence. We report the redirected differentiation of class I–restricted thymocytes into CD4⁺CD8^– helper-like T cells upon loss of Runx transcription factor complexes. A Runx-binding sequence within the Th-POK locus acts as a transcriptional silencer that is essential for Th-POK repression and for development of CD8⁺ T cells. Thus, Th-POK expression and genetic programming for T helper cell development are actively inhibited by Runx-dependent silencer activity, allowing for cytotoxic T cell differentiation. Identification of the transcription factors network in CD4 and CD8 lineage choice provides insight into how distinct T cell subsets are developed for regulating the adaptive immune system.