Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice

Abstract

Developing CD4⁺CD8⁺ double positive (DP) thymocytes differentiate either into CD4⁺ helper or CD8⁺ cytotoxic T cells, depending on the MHC-restriction specificity of their T-cell receptor (TCR). Classical models of CD4/CD8-lineage choice share the perspective that lineage choice occurs in thymocytes that express both Cd4 and Cd8 at the mRNA level (that is, transcriptionally Cd4⁺Cd8⁺) and results in the termination of transcription of one or the other co-receptor molecule as a consequence of the same TCR signals that mediate positive selection. Classical models are either stochastic or instructive, and experimental testing of these models has been extensive. However, crucial presumptions made by each classical model (stochastic selection, strength-of-signal or duration-of-signal models) have been experimentally contradicted. The kinetic signalling model of CD4/CD8-lineage choice differs in various respects from all classical models, as it postulates that TCR-signalled DP thymocytes first transiently terminate Cd8 gene expression and convert into Cd4⁺Cd8⁻ intermediate cells in which CD4/CD8-lineage choices are then made. Thus, positive selection and lineage choice are sequential events. CD4/CD8-lineage choice is determined in Cd4⁺Cd8⁻ intermediate cells by whether TCR-mediated positive selection signalling persists or ceases in the absence of Cd8 gene expression. Persistent TCR signalling drives CD4⁺ T-cell development, whereas disrupted TCR signalling permits signalling by interleukin-7 and other common cytokine-receptor γ-chain cytokines that drive CD8⁺ T-cell development. Recent advances in the molecular events that occur during CD4/CD8-lineage choice have identified a series of nuclear factors, including Th-POK (T-helper-inducing POZ/Kruppel-like factor), RUNX3 (runt-related transcription factor 3), TOX (thymus high-mobility group box protein) and GATA3 (GATA-binding protein 3), that are crucially involved in T-cell-lineage-fate determination. It is possible to integrate the activity of these nuclear factors into the kinetic signalling model to achieve an integrated picture of CD4/CD8-lineage choice on both a cellular and molecular level.