Key Points
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T cells with αβ T-cell receptors (TCRs) respond to foreign antigen in the form of short peptides that are bound to MHC class I or class II proteins. These TCRs are generated by somatic DNA rearrangements and random chain pairing, and hence, lack predictable specificity for their ligands.
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Optimal signalling in response to MHC ligands requires co-engagement of the TCR and either a CD4 (MHC-class-II-binding) or CD8 (MHC-class-I-binding) co-receptor. Immature thymocytes express both CD4 and CD8, but mature functional T cells express the co-receptor molecule that has an MHC-class specificity that matches that of the cell's TCR.
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During T-cell differentiation in the thymus, CD4+CD8+ double-positive (DP) precursors must make a lineage decision to become CD4+ (helper) or CD8+ (cytotoxic) T cells.
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Two models have been proposed to explain how a T cell that expresses a TCR with an unpredictable specificity emerges from the thymus with the required match between the MHC-binding preferences of TCR and co-receptor.
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The instruction model postulates that TCR–CD4 binding of a self-peptide–MHC-class-II ligand generates a signal that is distinct from that produced on co-binding of a TCR and CD8 molecule to a self-peptide–MHC-class-I ligand. These unique signals 'instruct' the precursor DP T cell to choose the correct lineage fate and develop into a CD4+ or CD8+ T cell.
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The selection model postulates that precursor DP T cells randomly choose a fate and lose expression of either CD4 or CD8. Further differentiation and survival depends on the cell having chosen correctly, so that it receives a signal from coordinate binding of the TCR and co-receptor to a self-peptide–MHC ligand. For TCRs that are specific for MHC class I, CD8 must be retained, whereas for TCRs with MHC class-II specificity, CD4 must be retained; the wrong choice dooms the cell at this checkpoint.
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Recent data indicate that a combination of these two models is a more accurate description of reality.
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The current 'strength of signal' model proposes that the intensity/duration of initial signalling dictates lineage choice; strong/long signalling leads to the CD4 pathway, whereas weaker/shorter signalling prompts the CD8 choice. This is generally correlated with MHC class-II versus class-I binding, respectively, because of differential association of LCK with the two co-receptors in DP thymocytes.
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A combination of negative selection and cell loss due to a failure to sustain signalling removes most of the cells that make 'incorrect' choices (overly strong MHC class-I reactivity that promotes CD4 lineage choice or very weak MHC class-II reactivity that leads to the CD8 lineage).
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The role of NOTCH proteins in this lineage-decision process remains controversial.
Abstract
Cell-fate decisions are controlled typically by conserved receptors that interact with co-evolved ligands. Therefore, the lineage-specific differentiation of immature CD4+CD8+ T cells into CD4+ or CD8+ mature T cells is unusual in that it is regulated by clonally expressed, somatically generated T-cell receptors (TCRs) of unpredictable fine specificity. Yet, each mature T cell generally retains expression of the co-receptor molecule (CD4 or CD8) that has an MHC-binding property that matches that of its TCR. Two models were proposed initially to explain this remarkable outcome — 'instruction' of lineage choice by initial signalling events or 'selection' after a stochastic fate decision that limits further development to cells with coordinated TCR and co-receptor specificities. Aspects of both models now appear to be correct; mistake-prone instruction of lineage choice precedes a subsequent selection step that filters out most incorrect decisions.
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Acknowledgements
I wish to thank the colleagues in my own laboratory and around the world whose experiments and discussions have helped to shape the ideas in this review. I also thank B.J. Fowlkes for reading a draft of this manuscript and making many very helpful suggestions for corrections, as well as improvements in presentation. Any errors that remain are my own.
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Glossary
- CO-RECEPTOR
-
A CD4 or CD8 molecule, which cooperatively recognizes an MHC class-II or class-I ligand, respectively, together with the antigen receptor (T-cell receptor) of a T cell.
- CLONAL EXPRESSION
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The presence of a particular somatically generated antigen receptor on a maturing T cell that is not shared with other independently developing precursors. This receptor is shared among the progeny of the mature cell after activation and cell division stimulated by foreign antigen.
- RECOMBINATION-ACTIVATING GENE
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(RAG). The product of this gene is involved in creating the double-strand DNA breaks that are necessary for producing the rearranged gene segments that encode the complete protein chains of T-cell and B-cell receptors.
- NEGATIVE SELECTION
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Active cell loss in the thymus, which is mediated by apoptosis induced by strong T-cell stimuli, particularly at later stages of maturation.
- POSITIVE SELECTION
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The maturation of immature CD4+CD8+ precursor thymocytes induced by T-cell receptor signals that result from binding to self-peptide–MHC ligands on thymic epithelial cells.
- PRONASE STRIPPING
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The treatment of cells with a powerful protease that removes surface protein molecules, followed by the analysis of surface phenotype immediately after such treatment and then after further culture.
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Germain, R. T-cell development and the CD4–CD8 lineage decision. Nat Rev Immunol 2, 309–322 (2002). https://doi.org/10.1038/nri798
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DOI: https://doi.org/10.1038/nri798