CD4/CD8 Lineage Commitment

Since the discovery that CD4 and CD8 T cells exhibit selective TCR specificity for MHC class II or I antigen-presenting molecules, respectively, the basis of CD4 and CD8 lineage commitment in the thymus has remained the focus of intense study. Studying the mechanism by which bipotential double-positive (DP) progenitors diverge into single-positive (SP) CD4 or CD8 thymocytes is important both for understanding formation of the adaptive immune system, as well as for elucidating the bipotential fate decisions in general. Current information strongly suggests that duration and intensity of TCR signaling controls lineage choice, as proposed by the kinetic signaling and quantitative instructive models, respectively. However, the molecular pathways by which alternate TCR signals trigger alternate lineage fates remain to be precisely elucidated. Recently, identification of the transcription factors, ThPOK (T helper-inducing POZ Krüppel) and Runx, as key regulators of lineage choice and lineage-specific gene expression has provided an important breakthrough in this regard. ThPOK is selectively expressed in class II-restricted cells at the CD4⁺8^lo stage and is necessary and sufficient to dictate development toward the CD4 lineage, while Runx3 is selectively required for CD8 T cell differentiation. Given the central role of ThPOK and Runx in lineage commitment and differentiation, understanding their upstream regulation and downstream modes of action is expected to reveal further important aspects of the molecular circuitry underlying CD4/CD8 lineage commitment. Accordingly, this article focuses mainly on the molecular basis of CD4/CD8 lineage commitment, describing the TCR signaling requirements and transcriptional regulatory circuits that control this process with a special emphasis on ThPOK and Runx.