Transcriptional reprogramming of mature CD4+ helper T cells generates distinct MHC class II–restricted cytotoxic T lymphocytes

CD4 + and CD8 + T cells are considered distinct functional lymphocyte subsets. Cheroutre and Mucida and their colleagues show that mature gut-associated CD4 + T cells lose ThPOK expression and reactivate CD8 cytolytic effector programs. 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.