TCRαβ thymocytes differentiate into either CD8αβ⁺ cytotoxic T lymphocytes or CD4⁺ helper T cells. This functional dichotomy is controlled by key transcription factors, including the helper T cell master regulator ThPOK, which suppresses the cytolytic program in major histocompatibility complex (MHC) class II–restricted CD4⁺ thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4⁺ T cells, even as they differentiate into effector helper T cell subsets. Here we found that the helper T cell fate was not fixed and that mature, antigen-stimulated CD4⁺ T cells terminated expression of the gene encoding ThPOK and reactivated genes of the CD8 lineage. This unexpected plasticity resulted in the post-thymic termination of the helper T cell program and the functional differentiation of distinct MHC class II–restricted CD4⁺ cytotoxic T lymphocytes.