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  • Review Article
  • Published:

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

Nature Reviews Immunology volume 8, pages 788–801 (2008)Cite this article

Key Points

  • 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.

Abstract

Following successful gene rearrangement at αβ T-cell receptor (TCR) loci, developing thymocytes express both CD4 and CD8 co-receptors and undergo a life-or-death selection event, which is known as positive selection, to identify cells that express TCRs with potentially useful ligand specificities. Positively selected thymocytes must then differentiate into either CD4+ helper T cells or CD8+ cytotoxic T cells, a crucial decision known as CD4/CD8-lineage choice. In this Review, we summarize recent advances in our understanding of the cellular and molecular events involved in lineage-fate decision and discuss them in the context of the major models of CD4/CD8-lineage choice.

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Figure 1: Overview of T-cell development in the thymus.
Figure 2: Classical models of CD4/CD8-lineage choice.
Figure 3: The kinetic signalling model of CD4/CD8-lineage choice.
Figure 4: Lineage-fate mapping according to the kinetic signalling model of CD4/CD8-lineage choice.
Figure 5: Regulation of Cd4 and Cd8 gene expression.
Figure 6: Environmental cues and nuclear factors that influence CD4/CD8-lineage choice.

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Acknowledgements

We thank our many colleagues who contributed to our current understanding of CD4/CD8 lineage-fate decisions in the thymus that we were unable to adequately acknowledge and reference in this Review. We are grateful to B. Erman, S. Sarafova, R. Bosselut and N. Taylor for many discussions and for their critical reading of the manuscript. This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research, USA.

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  1. Experimental Immunology Branch, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Alfred Singer, Stanley Adoro & Jung-Hyun Park

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  1. Alfred Singer
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Singer, A., Adoro, S. & Park, JH. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat Rev Immunol 8, 788–801 (2008). https://doi.org/10.1038/nri2416

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