Transcriptional reprogramming of mature CD4 super(+) helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes

TCR alpha beta thymocytes differentiate into either CD8 alpha beta super(+) cytotoxic T lymphocytes or CD4 super(+) 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 super(+) thymocytes. ThPOK continues to repress genes of the CD8 lineage in mature CD4 super(+) 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 super(+) 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 super(+) cytotoxic T lymphocytes.