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The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate

Nature volume 404, pages 506–510 (2000)Cite this article

A Corrigendum to this article was published on 07 September 2000

Abstract

Signals elicited by binding of the T-cell antigen receptor and the CD4/CD8 co-receptor to major histocompatibility complex (MHC) molecules control the generation of CD4+ (helper) or CD8+ (cytotoxic) T cells from thymic precursors that initially express both co-receptor proteins1. These precursors have unique, clonally distributed T-cell receptors with unpredictable specificity for the self-MHC molecules involved in this differentiation process2. However, the mature T cells that emerge express only the CD4 (MHC class II-binding) or CD8 (MHC class I-binding) co-receptor that complements the MHC class-specificity of the T-cell receptor. How this matching of co-receptor-defined lineage and T-cell-receptor specificity is achieved remains unknown1,3,4, as does whether signalling by the T-cell receptors, co-receptors and/or general cell-fate regulators such as Notch-1 (refs 5, 6) contributes to initial lineage choice, to subsequent differentiation processes or to both. Here we show that the CD4 versus CD8 lineage fate of immature thymocytes is controlled by the co-receptor-influenced duration of initial T-cell receptor-dependent signalling. Notch-1 does not appear to be essential for this fate determination, but it is selectively required for CD8+ T-cell maturation after commitment directed by T-cell receptors. This indicates that the signals constraining CD4 versus CD8 lineage decisions are distinct from those that support subsequent differentiation events such as silencing of co-receptor loci.

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Figure 1: Role of co-receptor in CD4/CD8 lineage choice.
Figure 2: Potent TCR ligands can promote thymocytes with an MHC class-I-restricted TCR to become CD4+ T cells.
Figure 3: The duration, not the magnitude, of TCR signalling dictates lineage choice.
Figure 4: Notch-1 is involved in post-commitment maturation of CD8 lineage T cells.

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References

  1. Robey, E. & Fowlkes, B. J. Selective events in T cell development. Annu. Rev. Immunol. 12, 675– 705 (1994).

    Article  CAS  Google Scholar 

  2. Davis, M. M. & Bjorkman, P. J. T-cell antigen receptor genes and T-cell recognition. Nature 334, 395– 402 (1988).

    Article  ADS  CAS  Google Scholar 

  3. von Boehmer, H. CD4/CD8 lineage commitment: back to instruction? J. Exp. Med. 183, 713–715 (1996).

    Article  CAS  Google Scholar 

  4. Chan, S., Correia-Neves, M., Benoist, C. & Mathis, D. CD4/CD8 lineage commitment: matching fate with competence. Immunol. Rev. 165, 195–207 ( 1998).

    Article  CAS  Google Scholar 

  5. Robey, E. et al. An activated form of Notch influences the choice between CD4 and CD8 T cell lineages. Cell 87, 483– 492 (1996).

    Article  CAS  Google Scholar 

  6. Deftos, M. L., He, Y. W., Ojala, E. W. & Bevan, M. J. Correlating notch signaling with thymocyte maturation. Immunity 9, 777–786 (1998).

    Article  CAS  Google Scholar 

  7. Kaye, J. et al. Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor. Nature 341, 746–749 (1989).

    Article  ADS  CAS  Google Scholar 

  8. Konig, R., Huang, L. Y. & Germain, R. N. MHC class II interaction with CD4 mediated by a region analogous to the MHC class I binding site for CD8. Nature 356, 796–798 (1992).

    Article  ADS  CAS  Google Scholar 

  9. Riberdy, J. M., Mostaghel, E. & Doyle, C. Disruption of the CD4-major histocompatibility complex class II interaction blocks the development of CD4(+) T cells in vivo. Proc. Natl Acad. Sci. USA 95, 4493– 4498 (1998).

    Article  ADS  CAS  Google Scholar 

  10. Anderson, G., Jenkinson, E. J., Moore, N. C. & Owen, J. J. MHC class II-positive epithelium and mesenchyme cells are both required for T-cell development in the thymus. Nature 362, 70–73 (1993).

    Article  ADS  CAS  Google Scholar 

  11. Lucas, B. & Germain, R. N. Unexpectedly complex regulation of CD4/CD8 coreceptor expression supports a revised model for CD4+CD8+ thymocyte differentiation. Immunity 5, 461– 477 (1996).

    Article  CAS  Google Scholar 

  12. Davis, C. B., Killeen, N., Crooks, M. E., Raulet, D. & Littman, D. R. Evidence for a stochastic mechanism in the differentiation of mature subsets of T lymphocytes. Cell 73, 237–247 ( 1993).

    Article  CAS  Google Scholar 

  13. Veillette, A., Zuniga-Pflucker, J. C., Bolen, J. B. & Kruisbeek, A. M. Engagement of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways. J. Exp. Med. 170, 1671–1680 ( 1989).

    Article  CAS  Google Scholar 

  14. Wiest, D. L. et al. Regulation of T cell receptor expression in immature CD4+CD8+ thymocytes by p56lck tyrosine kinase: basis for differential signaling by CD4 and CD8 in immature thymocytes expressing both coreceptor molecules. J. Exp. Med. 178, 1701–1712 (1993).

    Article  CAS  Google Scholar 

  15. Kisielow, P., Bluthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+8+ thymocytes. Nature 333, 742–746 ( 1988).

    Article  ADS  CAS  Google Scholar 

  16. Hogquist, K. A., Jameson, S. C. & Bevan, M. J. Strong agonist ligands for the T cell receptor do not mediate positive selection of functional CD8+ T cells. Immunity 3, 79–86 (1995 ).

    Article  CAS  Google Scholar 

  17. Teh, H. S. et al. Thymic major histocompatibility complex antigens and the alpha beta T- cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335, 229–233 ( 1988).

    Article  ADS  CAS  Google Scholar 

  18. Basson, M. A., Bommhardt, U., Cole, M. S., Tso, J. Y. & Zamoyska, R. CD3 ligation on immature thymocytes generates antagonist-like signals appropriate for CD8 lineage commitment, independently of T cell receptor specificity. J. Exp. Med. 187, 1249–1260 (1998).

    Article  CAS  Google Scholar 

  19. Merkenschlager, M. et al. How many thymocytes audition for selection? J. Exp. Med. 186, 1149–1158 (1997).

    Article  CAS  Google Scholar 

  20. Iwata, M., Kuwata, T., Mukai, M., Tozawa, Y. & Yokoyama, M. Differential induction of helper and killer T cells from isolated CD4+CD8+ thymocytes in suspension culture. Eur. J. Immunol. 26, 2081–2086 ( 1996).

    Article  CAS  Google Scholar 

  21. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221– 227 (1999).

    Article  CAS  Google Scholar 

  22. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547 –558 (1999).

    Article  CAS  Google Scholar 

  23. Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).

    Article  CAS  Google Scholar 

  24. Matechak, E. O., Killeen, N., Hedrick, S. M. & Fowlkes, B. J. MHC class II-specific T cells can develop in the CD8 lineage when CD4 is absent. Immunity 4, 337–347 (1996).

    Article  CAS  Google Scholar 

  25. Sharp, L. L., Schwarz, D. A., Bott, C. M., Marshall, C. J. & Hedrick, S. M. The influence of the MAPK pathway on T cell lineage commitment. Immunity 7, 609–618 (1997).

    Article  CAS  Google Scholar 

  26. Bommhardt, U., Basson, M. A., Krummrei, U. & Zamoyska, R. Activation of the extracellular signal-related kinase/mitogen-activated protein kinase pathway discriminates CD4 versus CD8 lineage commitment in the thymus. J. Immunol. 163, 715–722 (1999).

    CAS  PubMed  Google Scholar 

  27. Felli, M. P. et al. Expression pattern of notch1, 2 and 3 and jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Intl Immunol. 11 , 1017–1025 (1999).

    Article  CAS  Google Scholar 

  28. Beatus, P., Lundkvist, J., Oberg, C. & Lendahl, U. The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 126, 3925– 3935 (1999).

    CAS  PubMed  Google Scholar 

  29. Inaba, M. et al. Distinct mechanisms of neonatal tolerance induced by dendritic cells and thymic B cells. J. Exp. Med. 173, 549–559 (1991).

    Article  CAS  Google Scholar 

  30. Ouyang, W. et al. Inhibition of Th1 development mediated by GATA-3 through an IL-4- independent mechanism. Immunity 9, 745–755 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was partially support by grants from the Illinois Department of Public Health and from NIH to L.M. and American Cancer Society and the Arthritis Foundation to C.D. K.Y. was supported in part by a fellowship from the Japan Society for the Promotion of Science. We thank B.J. Fowlkes and R. H. Schwartz for their helpful comments on this manuscript, J. Delon for insightful suggestions concerning data interpretation, and M. Verma for generating the antisense Notch-1 construct.

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Authors and Affiliations

  1. Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892 , Maryland, USA

    Koji Yasutomo & Ronald N. Germain

  2. Department of Immunology, Duke University Medical Centre, Durham, 27710 , North Carolina, USA

    Carolyn Doyle

  3. Cancer Immunology Program, Cardinal Bernardin Cancer Centre, Loyola University Medical Centre, Maywood , 60153, Illinois, USA

    Lucio Miele

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  1. Koji Yasutomo
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Correspondence to Ronald N. Germain.

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Yasutomo, K., Doyle, C., Miele, L. et al. The duration of antigen receptor signalling determines CD4+ versus CD8+ T-cell lineage fate. Nature 404, 506–510 (2000). https://doi.org/10.1038/35006664

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