CD4–CD8 differentiation in the thymus: connecting circuits and building memories

The proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present a brief overview of the transcriptional control of this process, with emphasis on two issues. The study of Cd4 expression, that had previously generated important paradigms for transcriptional regulation in eukaryotic cells, now brings new twists to the concept of ‘epigenetic memory’. And connections are emerging between transcriptional regulators critical for commitment to either lineage. The present review attempts to integrate these findings and discusses the still elusive mechanisms that match CD4–CD8 lineage differentiation to MHC specificity.

► An enhancer active in the thymus imprints epigenetic memory within the Cd4 locus.
► A Thpok-Runx3 regulatory loop controls CD4–CD8 lineage commitment and contributes to maintain lineage identity.
► Transcription factors Mazr and Runx1 contribute to the Thpok-Runx3 commitment loop.
► Newly indentified transcription factors promote Thpok and Runx3 expression and CD4 or CD8 lineage specification.