Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

T-cell development and the CD4–CD8 lineage decision

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • Recent data indicate that a combination of these two models is a more accurate description of reality.

  • 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.

  • 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).

  • 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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overall scheme of T-cell development in the thymus.
Figure 2: Instruction' and 'stochastic' models for the development of mature T cells with coordinated TCR and co-receptor specificities.
Figure 3: Complex pattern of CD4 and CD8 expression on positively selected thymocytes.
Figure 4: 'Strength of signal' model for the development of mature T cells with coordinated TCR and co-receptor specificities.
Figure 5: Two different roles for MAPK1 in thymocyte development.

Similar content being viewed by others

References

  1. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Germain, R. N. MHC-dependent antigen processing and peptide presentation: providing ligands for T-lymphocyte activation. Cell 76, 287–299 (1994).

    CAS  PubMed  Google Scholar 

  3. Biddison, W. E., Rao, P. E., Talle, M. A., Goldstein, G. & Shaw, S. Possible involvement of the OKT4 molecule in T-cell recognition of class II HLA antigens. Evidence from studies of cytotoxic T lymphocytes specific for SB antigens. J. Exp. Med. 156, 1065–1076 (1982).

    CAS  PubMed  Google Scholar 

  4. Swain, S. L. T-cell subsets and the recognition of MHC class. Immunol. Rev. 74, 129–142 (1983).

    CAS  PubMed  Google Scholar 

  5. Janeway, C. A. Jr. The T-cell receptor as a multicomponent signalling machine: CD4/CD8 coreceptors and CD45 in T-cell activation. Annu. Rev. Immunol. 10, 645–674 (1992).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  7. Kruisbeek, A. M. et al. Absence of the Lyt-2L3T4+ lineage of T cells in mice treated neonatally with anti-I-A correlates with absence of intrathymic I-A-bearing antigen-presenting-cell function. J. Exp. Med. 161, 1029–1047 (1985).One of the very first papers to show that the class of MHC molecule that is recognized controls the development of a particular mature co-receptor-defined T-cell subset.

    CAS  PubMed  Google Scholar 

  8. Teh, H. S. et al. Thymic major histocompatibility complex antigens and the αβ T-cell receptor determine the CD4/CD8 phenotype of T cells. Nature 335, 229–233 (1988).The first use of TCR-transgenic mice to reveal the relationship between MHC class-specificity in foreign antigen recognition and co-receptor-defined lineage development in the thymus.

    CAS  PubMed  Google Scholar 

  9. Marusic-Galesic, S., Longo, D. L. & Kruisbeek, A. M. Preferential differentiation of T-cell receptor specificities based on the MHC glycoproteins encountered during development. Evidence for positive selection. J. Exp. Med. 169, 1619–1630 (1989).

    CAS  PubMed  Google Scholar 

  10. 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).An extension of the results of reference 8 to MHC class-II recognition and CD4+ single-positive T-cell development.

    CAS  PubMed  Google Scholar 

  11. Robey, E. A., Fowlkes, B. J. & Pardoll, D. M. Molecular mechanisms for lineage commitment in T-cell development. Semin. Immunol. 2, 25–34 (1990).

    CAS  PubMed  Google Scholar 

  12. Borgulya, P., Kishi, H., Müller, U., Kirberg, J. & von Boehmer, H. Development of the CD4 and CD8 lineage of T cells: instruction versus selection. EMBO J. 10, 913–918 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Robey, E. A. et al. Thymic selection in CD8-transgenic mice supports an instructive model for commitment to a CD4 or CD8 lineage. Cell 64, 99–107 (1991).References 11–13 set out the original proposals for the 'instruction' versus 'selection' models of lineage commitment and development. They also provided the first experimental tests of the models, which looked for 'rescue' with co-receptor transgenes.

    CAS  PubMed  Google Scholar 

  14. 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).

    CAS  PubMed  Google Scholar 

  15. Chan, S. H., Cosgrove, D., Waltzinger, C., Benoist, C. & Mathis, D. Another view of the selective model of thymocyte selection. Cell 73, 225–236 (1993).

    CAS  PubMed  Google Scholar 

  16. van Meerwijk, J. P. & Germain, R. N. Development of mature CD8+ thymocytes: selection rather than instruction? Science 261, 911–915 (1993).References 15 and 16 conclude that stochastic choice/selection is more probable than instruction, based on the appearance of transitional-phenotype cells in various MHC-deficient mice.

    CAS  PubMed  Google Scholar 

  17. von Boehmer, H. & Kisielow, P. Lymphocyte lineage commitment: instruction versus selection. Cell 73, 207–208 (1993).

    CAS  PubMed  Google Scholar 

  18. Chan, S. H., Benoist, C. & Mathis, D. In favor of the selective model of positive selection. Semin. Immunol. 6, 241–248 (1994).

    CAS  PubMed  Google Scholar 

  19. van Meerwijk, J. P. M., O'Connell, E. M. & Germain, R. N. Evidence for lineage commitment and initiation of positive selection by thymocytes with intermediate surface phenotypes. J. Immunol. 154, 6314–6323 (1995).

    CAS  PubMed  Google Scholar 

  20. Kersh, G. J. & Hedrick, S. M. Role of TCR specificity in CD4 versus CD8 lineage commitment. J. Immunol. 154, 1057–1068 (1995).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Itano, A. et al. The cytoplasmic domain of CD4 promotes the development of CD4-lineage T cells. J. Exp. Med. 183, 731–741 (1996).

    CAS  PubMed  Google Scholar 

  23. 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).References 22 and 23 contain the initial descriptions of the 'strength of signal' model.

    CAS  PubMed  Google Scholar 

  24. Ohoka, Y. et al. Regulation of thymocyte lineage commitment by the level of classical protein kinase C activity. J. Immunol. 158, 5707–5716 (1997).

    CAS  PubMed  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).This study provides clear evidence that high MAPK activity favours the development of CD4+ single-positive T cells and low MAPK activity favours the development of CD8+ single-positive T cells.

    CAS  PubMed  Google Scholar 

  26. Bommhardt, U., Cole, M. S., Tso, J. Y. & Zamoyska, R. Signals through CD8 or CD4 can induce commitment to the CD4 lineage in the thymus. Eur. J. Immunol. 27, 1152–1163 (1997).

    CAS  PubMed  Google Scholar 

  27. Goldrath, A. W., Hogquist, K. A. & Bevan, M. J. CD8-lineage commitment in the absence of CD8. Immunity 6, 633–642 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sebzda, E., Choi, M., Fung-Leung, W. P., Mak, T. W. & Ohashi, P. S. Peptide-induced positive selection of TCR-transgenic thymocytes in a coreceptor-independent manner. Immunity 6, 643–653 (1997).

    CAS  PubMed  Google Scholar 

  29. 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).

    CAS  PubMed  Google Scholar 

  30. Basson, M. A., Bommhardt, U., Mee, P. J., Tybulewicz, V. L. & Zamoyska, R. Molecular requirements for lineage commitment in the thymus — antibody-mediated receptor engagements reveal a central role for Lck in lineage decisions. Immunol. Rev. 165, 181–194 (1998).

    CAS  PubMed  Google Scholar 

  31. Legname, G. et al. Inducible expression of a p56Lck transgene reveals a central role for Lck in the differentiation of CD4+ SP thymocytes. Immunity 12, 537–546 (2000).

    CAS  PubMed  Google Scholar 

  32. Hernandez-Hoyos, G., Sohn, S. J., Rothenberg, E. V. & Alberola-Ila, J. Lck activity controls CD4/CD8 T-cell lineage commitment. Immunity 12, 313–322 (2000).

    CAS  PubMed  Google Scholar 

  33. Yasutomo, K., Doyle, C., Miele, L., Fuchs, C. & Germain, R. N. The duration of antigen-receptor signalling determines CD4+ versus CD8+ T-cell lineage fate. Nature 404, 506–510 (2000).This study used a re-aggregate culture system to separate early and late signals through the TCR and co-receptor in controlling thymocyte development. It showed that signal duration during the initiation of positive selection 'instructs' lineage choice and is controlled by co-operation between the TCR and co-receptors.

    CAS  PubMed  Google Scholar 

  34. Brugnera, E. et al. Coreceptor reversal in the thymus: signaled CD4+8+ thymocytes initially terminate CD8 transcription even when differentiating into CD8+ T cells. Immunity 13, 59–71 (2000).

    CAS  PubMed  Google Scholar 

  35. Itano, A. & Robey, E. Highly efficient selection of CD4- and CD8-lineage thymocytes supports an instructive model of lineage commitment. Immunity 12, 383–389 (2000).

    CAS  PubMed  Google Scholar 

  36. Watanabe, N., Arase, H., Onodera, M., Ohashi, P. S. & Saito, T. The quantity of TCR signal determines positive selection and lineage commitment of T cells. J. Immunol. 165, 6252–6261 (2000).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  38. Pui, J. C. et al. Notch1 expression in early lymphopoiesis influences B- versus T-lineage determination. Immunity 11, 299–308 (1999).

    CAS  PubMed  Google Scholar 

  39. Wilson, A., MacDonald, H. R. & Radtke, F. Notch-1-deficient common lymphoid precursors adopt a B-cell fate in the thymus. J. Exp. Med. 194, 1003–1012 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Michie, A. M. et al. Clonal characterization of a bipotent T-cell and NK-cell progenitor in the mouse fetal thymus. J. Immunol. 164, 1730–1733 (2000).

    CAS  PubMed  Google Scholar 

  41. Godfrey, D. I., Kennedy, J., Suda, T. & Zlotnik, A. A developmental pathway involving four phenotypically and functionally distinct subsets of CD3CD4CD8 triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 150, 4244–4252 (1993).

    CAS  PubMed  Google Scholar 

  42. Groettrup, M. et al. A novel disulfide-linked heterodimer on pre-T cells consists of the T-cell receptor β-chain and a 33 kD glycoprotein. Cell 75, 283–294 (1993).

    CAS  PubMed  Google Scholar 

  43. von Boehmer, H. & Fehling, H. J. Structure and function of the pre-T-cell receptor. Annu. Rev. Immunol. 15, 433–452 (1997).

    CAS  PubMed  Google Scholar 

  44. Aifantis, I., Feinberg, J., Fehling, H. J., Di Santo, J. P. & von Boehmer, H. Early T-cell receptor-β gene expression is regulated by the pre-T-cell-receptor–CD3 complex. J. Exp. Med. 190, 141–144 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Mombaerts, P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    CAS  PubMed  Google Scholar 

  46. Shinkai, Y. et al. Restoration of T-cell development in RAG-2-deficient mice by functional TCR transgenes. Science 259, 822–825 (1993).

    CAS  PubMed  Google Scholar 

  47. van Oers, N. S., von Boehmer, H. & Weiss, A. The pre-T-cell receptor (TCR) complex is functionally coupled to the TCR-ζ subunit. J. Exp. Med. 182, 1585–1590 (1995).

    CAS  PubMed  Google Scholar 

  48. Negishi, I. et al. Essential role for ZAP-70 in both positive and negative selection of thymocytes. Nature 376, 435–438 (1995).

    CAS  PubMed  Google Scholar 

  49. van Oers, N. S., Lowin-Kropf, B., Finlay, D., Connolly, K. & Weiss, A. αβ T-cell development is abolished in mice lacking both Lck and Fyn protein tyrosine kinases. Immunity 5, 429–436 (1996).

    CAS  PubMed  Google Scholar 

  50. Clements, J. L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T-cell development. Science 281, 416–419 (1998).

    CAS  PubMed  Google Scholar 

  51. von Boehmer, H., Teh, H. S. & Kisielow, P. The thymus selects the useful, neglects the useless and destroys the harmful. Immunol. Today 10, 57–61 (1989).A seminal description of the TCR-dependent selection events that control thymocyte fate.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zerrahn, J., Held, W. & Raulet, D. H. The MHC reactivity of the T-cell repertoire prior to positive and negative selection. Cell 88, 627–636 (1997).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  55. Anderson, S. J., Levin, S. D. & Perlmutter, R. M. Involvement of the protein tyrosine kinase p56lck in T-cell signaling and thymocyte development. Adv. Immunol. 56, 151–178 (1994).

    CAS  PubMed  Google Scholar 

  56. Weiss, A. & Littman, D. R. Signal transduction by lymphocyte antigen receptors. Cell 76, 263–274 (1994).

    CAS  PubMed  Google Scholar 

  57. Kane, L. P., Lin, J. & Weiss, A. Signal transduction by the TCR for antigen. Curr. Opin. Immunol. 12, 242–249 (2000).

    CAS  PubMed  Google Scholar 

  58. Zhang, W., Sloan-Lancaster, J., Kitchen, J., Trible, R. P. & Samelson, L. E. LAT: the ZAP-70 tyrosine kinase substrate that links T-cell receptor to cellular activation. Cell 92, 83–92 (1998).

    CAS  PubMed  Google Scholar 

  59. Kuo, C. T. & Leiden, J. M. Transcriptional regulation of T-lymphocyte development and function. Annu. Rev. Immunol. 17, 149–187 (1999).

    CAS  PubMed  Google Scholar 

  60. Germain, R. N. & Stefanova, I. The dynamics of T-cell receptor signaling: complex orchestration and the key roles of tempo and cooperation. Annu. Rev. Immunol. 17, 467–522 (1999).

    CAS  PubMed  Google Scholar 

  61. Germain, R. N. The T-cell receptor for antigen: signaling and ligand discrimination. J. Biol. Chem. 276, 35223–35226 (2001).

    CAS  PubMed  Google Scholar 

  62. Madrenas, J., Chau, L. A., Smith, J., Bluestone, J. A. & Germain, R. N. The efficiency of CD4 recruitment to ligand-engaged TCR controls the agonist/partial agonist properties of peptide–MHC molecule ligands. J. Exp. Med. 185, 219–229 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hampl, J., Chien, Y. H. & Davis, M. M. CD4 augments the response of a T cell to agonist but not to antagonist ligands. Immunity 7, 379–385 (1997).

    CAS  PubMed  Google Scholar 

  64. Bosselut, R. et al. Association of the adaptor molecule LAT with CD4 and CD8 coreceptors identifies a new coreceptor function in T-cell receptor signal transduction. J. Exp. Med. 190, 1517–1526 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Sawada, S. & Littman, D. R. Identification and characterization of a T-cell-specific enhancer adjacent to the murine CD4 gene. Mol. Cell. Biol. 11, 5506–5515 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Sawada, S., Scarborough, J. D., Killeen, N. & Littman, D. R. A lineage-specific transcriptional silencer regulates CD4 gene expression during T-lymphocyte development. Cell 77, 917–929 (1994).

    CAS  PubMed  Google Scholar 

  67. Ellmeier, W., Sunshine, M. J., Losos, K., Hatam, F. & Littman, D. R. An enhancer that directs lineage-specific expression of CD8 in positively selected thymocytes and mature T cells. Immunity 7, 537–547 (1997).

    CAS  PubMed  Google Scholar 

  68. Ellmeier, W., Sawada, S. & Littman, D. R. The regulation of CD4 and CD8 coreceptor gene expression during T-cell development. Annu. Rev. Immunol. 17, 523–554 (1999).

    CAS  PubMed  Google Scholar 

  69. Hostert, A. et al. A CD8 genomic fragment that directs subset-specific expression of CD8 in transgenic mice. J. Immunol. 158, 4270–4281 (1997).

    CAS  PubMed  Google Scholar 

  70. Hostert, A. et al. A region in the CD8 gene locus that directs expression to the mature CD8 T-cell subset in transgenic mice. Immunity 7, 525–536 (1997).

    CAS  PubMed  Google Scholar 

  71. Adlam, M., Duncan, D. D., Ng, D. K. & Siu, G. Positive selection induces CD4 promoter and enhancer function. Int. Immunol. 9, 877–887 (1997).

    CAS  PubMed  Google Scholar 

  72. Hostert, A. et al. Hierarchical interactions of control elements determine CD8α gene expression in subsets of thymocytes and peripheral T cells. Immunity 9, 497–508 (1998).

    CAS  PubMed  Google Scholar 

  73. Kim, H. K. & Siu, G. The notch pathway intermediate HES-1 silences CD4 gene expression. Mol. Cell. Biol. 18, 7166–7175 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Zou, Y. R. et al. Epigenetic silencing of CD4 in T cells committed to the cytotoxic lineage. Nature Genet. 29, 332–336 (2001).

    CAS  PubMed  Google Scholar 

  75. Leung, R. K. et al. Deletion of the CD4 silencer element supports a stochastic mechanism of thymocyte lineage commitment. Nature Immunol. 2, 1167–1173 (2001).This report argues for a stochastic/selection model, on the basis of MHC class-II-dependent production of CD8-lineage cells after the elimination of CD4 silencer function. See the text and legend to Fig. 4 for an alternative interpretation of these data that is consistent with an instruction model.

    CAS  Google Scholar 

  76. Davis, C. B. & Littman, D. R. Thymocyte lineage commitment: is it instructed or stochastic? Curr. Opin. Immunol. 6, 266–272 (1994).

    CAS  PubMed  Google Scholar 

  77. Itano, A., Kioussis, D. & Robey, E. Stochastic component to development of class I major-histocompatibility-complex-specific T cells. Proc. Natl Acad. Sci. USA 91, 220–224 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Robey, E., Itano, A., Fanslow, W. C. & Fowlkes, B. J. Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice. J. Exp. Med. 179, 1997–2004 (1994).

    CAS  PubMed  Google Scholar 

  79. Guidos, C. J., Danska, J. S., Fathman, C. G. & Weissman, I. L. T-cell-receptor-mediated negative selection of autoreactive T-lymphocyte precursors occurs after commitment to the CD4 or CD8 lineages. J. Exp. Med. 172, 835–845 (1990).An initial description of intermediate surface-antigen phenotypes that accompany the double-positive to single-positive transition. The concept of 'linear' co-receptor loss that arose from this paper was responsible for the difficulty in correctly interpreting later studies of intermediate-phenotype cells in MHC-deficient mice.

    CAS  PubMed  Google Scholar 

  80. Crump, A. L., Grusby, M. J., Glimcher, L. H. & Cantor, H. Thymocyte development in major-histocompatibility-complex-deficient mice: evidence for stochastic commitment to the CD4 and CD8 lineages. Proc. Natl Acad. Sci. USA 90, 10739–10743 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Suzuki, H., Punt, J. A., Granger, L. G. & Singer, A. Asymmetric signaling requirements for thymocyte commitment to the CD4+ versus CD8+ T-cell lineages: a new perspective on thymic commitment and selection. Immunity 2, 413–425 (1995).

    CAS  PubMed  Google Scholar 

  82. Lundberg, K., Heath, W., Köntgen, F., Carbone, F. & Shortman, K. Intermediate steps in positive selection: differentiation of CD4+CD8intTCRint thymocytes into CD4CD8+TCRhi thymocytes. J. Exp. Med. 181, 1643–1651 (1995).

    CAS  PubMed  Google Scholar 

  83. 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).This paper proposes a complex, non-linear pattern of changes in co-receptor expression during thymocyte maturation that accounts for the existence of transitional cells in MHC-deficient animals without postulating stochastic choice. This model also explains the data in references 81 and 82 , which show that CD4+CD8low thymocytes can generate both CD4+ and CD8+ single-positive T cells.

    CAS  PubMed  Google Scholar 

  84. Barthlott, T., Kohler, H., Pircher, H. & Eichmann, K. Differentiation of CD4highCD8low coreceptor-skewed thymocytes into mature CD8 single-positive cells independent of MHC class-I recognition. Eur. J. Immunol. 27, 2024–2032 (1997).

    CAS  PubMed  Google Scholar 

  85. Correia-Neves, M., Mathis, D. & Benoist, C. A molecular chart of thymocyte positive selection. Eur. J. Immunol. 31, 2583–2592 (2001).

    CAS  PubMed  Google Scholar 

  86. Seong, R. H., Chamberlain, J. W. & Parnes, J. R. Signal for T-cell differentiation to a CD4 cell lineage is delivered by CD4 transmembrane region and/or cytoplasmic tail. Nature 356, 718–720 (1992).

    CAS  PubMed  Google Scholar 

  87. Itano, A., Cado, D., Chan, F. K. & Robey, E. A role for the cytoplasmic tail of the β-chain of CD8 in thymic selection. Immunity 1, 287–290 (1994).

    CAS  PubMed  Google Scholar 

  88. 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).The first report of marked asymmetry of Lck association with CD4 versus CD8 in thymocytes.

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  Google Scholar 

  90. Pircher, H., Ohashi, P. S., Boyd, R. L., Hengartner, H. & Brduscha, K. Evidence for a selective and multi-step model of T-cell differentiation: CD4+CD8low thymocytes selected by a transgenic T-cell receptor on major histocompatibility complex class I molecules. Eur. J. Immunol. 24, 1982–1987 (1994).

    CAS  PubMed  Google Scholar 

  91. Kisielow, P. & Miazek, A. Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T-cell receptor. J. Exp. Med. 181, 1975–1984 (1995).

    CAS  PubMed  Google Scholar 

  92. Wilkinson, R. W., Anderson, G., Owen, J. J. & Jenkinson, E. J. Positive selection of thymocytes involves sustained interactions with the thymic microenvironment. J. Immunol. 155, 5234–5240 (1995).

    CAS  PubMed  Google Scholar 

  93. Kirberg, J., Berns, A. & von Boehmer, H. Peripheral T-cell survival requires continual ligation of the T-cell receptor to major-histocompatibility-complex-encoded molecules. J. Exp. Med. 186, 1269–1275 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Yasutomo, K., Lucas, B. & Germain, R. N. TCR signaling for initiation and completion of thymocyte positive selection has distinct requirements for ligand quality and presenting-cell type. J. Immunol. 165, 3015–3022 (2000).

    CAS  PubMed  Google Scholar 

  95. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kisielow, P., Blüthmann, H., Staerz, U. D., Steinmetz, M. & von Boehmer, H. Tolerance in T-cell-receptor transgenic mice involves deletion of nonmature CD4+CD8+ thymocytes. Nature 333, 742–746 (1988).

    CAS  PubMed  Google Scholar 

  97. Wilkinson, B. & Kaye, J. Requirement for sustained MAPK signaling in both CD4 and CD8 lineage commitment: a threshold model. Cell. Immunol. 211, 86–95 (2001).

    CAS  PubMed  Google Scholar 

  98. Shao, H., Wilkinson, B., Lee, B., Han, P. C. & Kaye, J. Slow accumulation of active mitogen-activated protein kinase during thymocyte differentiation regulates the temporal pattern of transcription-factor gene expression. J. Immunol. 163, 603–610 (1999).

    CAS  PubMed  Google Scholar 

  99. Chan, S., Correia-Neves, M., Dierich, A., Benoist, C. & Mathis, D. Visualization of CD4/CD8 T-cell commitment. J. Exp. Med. 188, 2321–2333 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  101. 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 

  102. Shao, H., Rubin, E. M., Chen, L. Y. & Kaye, J. A role for Ras signaling in coreceptor regulation during differentiation of a double-positive thymocyte cell line. J. Immunol. 159, 5773–5776 (1997).

    CAS  PubMed  Google Scholar 

  103. Lorenz, U., Ravichandran, K. S., Burakoff, S. J. & Neel, B. G. Lack of SHPTP1 results in src-family kinase hyperactivation and thymocyte hyperresponsiveness. Proc. Natl Acad. Sci. USA 93, 9624–9629 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Pani, G., Fischer, K. D., Mlinaric-Rascan, I. & Siminovitch, K. A. Signaling capacity of the T-cell antigen receptor is negatively regulated by the PTP1C tyrosine phosphatase. J. Exp. Med. 184, 839–852 (1996).

    CAS  PubMed  Google Scholar 

  105. Plas, D. R. et al. Direct regulation of ZAP-70 by SHP-1 in T-cell antigen-receptor signaling. Science 272, 1173–1176 (1996).

    CAS  PubMed  Google Scholar 

  106. Carter, J. D., Neel, B. G. & Lorenz, U. The tyrosine phosphatase SHP-1 influences thymocyte selection by setting TCR signaling thresholds. Int. Immunol. 11, 1999–2014 (1999).

    CAS  PubMed  Google Scholar 

  107. Zhang, J. et al. Involvement of the SHP-1 tyrosine phosphatase in regulation of T-cell selection. J. Immunol. 163, 3012–3021 (1999).

    CAS  PubMed  Google Scholar 

  108. Johnson, K. G., LeRoy, F. G., Borysiewicz, L. K. & Matthews, R. J. TCR signaling thresholds regulating T-cell development and activation are dependent upon SHP-1. J. Immunol. 162, 3802–3813 (1999).

    CAS  PubMed  Google Scholar 

  109. Plas, D. R. et al. Cutting edge: the tyrosine phosphatase SHP-1 regulates thymocyte positive selection. J. Immunol. 162, 5680–5684 (1999).

    CAS  PubMed  Google Scholar 

  110. Chiang, G. G. & Sefton, B. M. Specific dephosphorylation of the Lck tyrosine-protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. J. Biol. Chem. 276, 23173–23178 (2001).

    CAS  PubMed  Google Scholar 

  111. 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. Int. Immunol. 11, 1017–1025 (1999).

    CAS  PubMed  Google Scholar 

  112. Robey, E. Notch in vertebrates. Curr. Opin. Genet. Dev. 7, 551–557 (1997).

    CAS  PubMed  Google Scholar 

  113. Osborne, B. & Miele, L. Notch and the immune system. Immunity 11, 653–663 (1999).

    CAS  PubMed  Google Scholar 

  114. Anderson, G., Pongracz, J., Parnell, S. & Jenkinson, E. J. Notch-ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T-cell receptor signaling. Eur. J. Immunol. 31, 3349–3354 (2001).

    CAS  PubMed  Google Scholar 

  115. Robey, E. et al. An activated form of Notch influences the choice between CD4 and CD8 T-cell lineages. Cell 87, 483–492 (1996).This study concludes, from the phenotype of mice that express an active Notch1 transgene, that Notch signaling has a central role in CD4–CD8 lineage choice.

    CAS  PubMed  Google Scholar 

  116. Jimenez, E. et al. Distinct mechanisms contribute to generate and change the CD4:CD8 cell ratio during thymus development: a role for the Notch ligand, Jagged1. J. Immunol. 166, 5898–5908 (2001).

    CAS  PubMed  Google Scholar 

  117. Deftos, M. L., Huang, E., Ojala, E. W., Forbush, K. A. & Bevan, M. J. Notch1 signaling promotes the maturation of CD4+ and CD8+ SP thymocytes. Immunity 13, 73–84 (2000).This study presents evidence from a different active Notch1 -transgenic model that Notch contributes to the survival of both developing CD4- and CD8-lineage cells; it argues against the concept that Notch has a selective role in the CD8 pathway.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wolfer, A. et al. Inactivation of Notch 1 in immature thymocytes does not perturb CD4+ or CD8+ T-cell development. Nature Immunol. 2, 235–241 (2001).Using a conditional deletion strategy, it is shown that Notch1 expression beyond the double-negative stage is not important in normal CD4+ and CD8+ single-positive T-cell development.

    CAS  Google Scholar 

  119. Izon, D. J. et al. Notch1 regulates maturation of CD4+ and CD8+ thymocytes by modulating TCR signal strength. Immunity 14, 253–264 (2001).

    CAS  PubMed  Google Scholar 

  120. Davey, G. M. et al. Preselection thymocytes are more sensitive to T-cell receptor stimulation than mature T cells. J. Exp. Med. 188, 1867–1874 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Lucas, B., Stefanova, I., Yasutomo, K., Dautigny, N. & Germain, R. N. Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T-cell repertoire. Immunity 10, 367–376 (1999).

    CAS  PubMed  Google Scholar 

  122. Rothenberg, E. V. Stepwise specification of lymphocyte developmental lineages. Curr. Opin. Genet. Dev. 10, 370–379 (2000).

    CAS  PubMed  Google Scholar 

  123. Matzinger, P. & Guerder, S. Does T-cell tolerance require a dedicated antigen-presenting cell? Nature 338, 74–76 (1989).

    CAS  PubMed  Google Scholar 

  124. Sant'Angelo, D. B. et al. A molecular map of T-cell development. Immunity 9, 179–186 (1998).

    CAS  PubMed  Google Scholar 

  125. Alberola-Ila, J., Forbush, K. A., Seger, R., Krebs, E. G. & Perlmutter, R. M. Selective requirement for MAP kinase activation in thymocyte differentiation. Nature 373, 620–623 (1995).

    CAS  PubMed  Google Scholar 

  126. Alberola-Ila, J., Hogquist, K. A., Swan, K. A., Bevan, M. J. & Perlmutter, R. M. Positive and negative selection invoke distinct signaling pathways. J. Exp. Med. 184, 9–18 (1996).

    CAS  PubMed  Google Scholar 

  127. O'Shea, C. C., Crompton, T., Rosewell, I. R., Hayday, A. C. & Owen, M. J. Raf regulates positive selection. Eur. J. Immunol. 26, 2350–2355 (1996).

    CAS  PubMed  Google Scholar 

  128. Mariathasan, S., Ho, S. S., Zakarian, A. & Ohashi, P. S. Degree of ERK activation influences both positive and negative thymocyte selection. Eur. J. Immunol. 30, 1060–1068 (2000).

    CAS  PubMed  Google Scholar 

  129. Gong, Q. et al. Disruption of T-cell signaling networks and development by Grb2 haploid insufficiency. Nature Immunol. 2, 29–36 (2001).

    CAS  Google Scholar 

  130. Mariathasan, S. et al. Duration and strength of extracellular signal-regulated kinase signals are altered during positive versus negative thymocyte selection. J. Immunol. 167, 4966–4973 (2001).

    CAS  PubMed  Google Scholar 

  131. Bain, G. et al. Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras–ERK MAPK cascade. Nature Immunol. 2, 165–171 (2001).

    CAS  Google Scholar 

  132. Engel, I., Johns, C., Bain, G., Rivera, R. R. & Murre, C. Early thymocyte development is regulated by modulation of E2A protein activity. J. Exp. Med. 194, 733–745 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Pages, G. et al. Defective thymocyte maturation in p44 MAP kinase (Erk-1)-knockout mice. Science 286, 1374–1377 (1999).

    CAS  PubMed  Google Scholar 

  134. 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).

    CAS  PubMed  Google Scholar 

  135. Bendelac, A., Matzinger, P., Seder, R. A., Paul, W. E. & Schwartz, R. H. Activation events during thymic selection. J. Exp. Med. 175, 731–742 (1992).

    CAS  PubMed  Google Scholar 

  136. Swat, W., Dessing, M., Baron, A., Kisielow, P. & von Boehmer, H. Phenotypic changes accompanying positive selection of CD4+CD8+ thymocytes. Eur. J. Immunol. 22, 2367–2372 (1992).

    CAS  PubMed  Google Scholar 

  137. Koch, U. et al. Subversion of the T/B lineage decision in the thymus by lunatic-fringe-mediated inhibition of Notch-1. Immunity 15, 225–236 (2001).

    CAS  PubMed  Google Scholar 

  138. Linette, G. P. et al. Bcl-2 is upregulated at the CD4+CD8+ stage during positive selection and promotes thymocyte differentiation at several control points. Immunity 1, 197–205 (1994).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Related links

Related links

DATABASES

InterPro

ITAM

NF-κB

SH2 domain

LocusLink

Bcl2

CD3/ζ

CD4

Cd4

CD8

Cd8

CD25

CD44

CD69

Deltex

DLK1

E2A

EGR1

Fyn

HES

HES1

HY antigen

ID3

JAG1

JAG2

JNK

LAT

LCK

Lck

Lunatic fringe

MAPK1

Mapk

Mek1

MHC class I

MHC class II

NFAT

Notch1

Notch2

Pkc

presenilin

Rag

RAG1

RAG2

SHP1

Slp76

ZAP70

Zap70

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

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

(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

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

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

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Germain, R. T-cell development and the CD4–CD8 lineage decision. Nat Rev Immunol 2, 309–322 (2002). https://doi.org/10.1038/nri798

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri798

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing