Differential Involvement of Protein Tyrosine Kinases p56lck and p59fyn in T Cell Development

  • Nicolai S. C. van Oers
  • Alex M. Garvin
  • Michael P. Cooke
  • Craig B. Davis
  • D. R. Littman
  • Roger M. Perlmutter
  • Hung-Sia Teh
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 323)


Mature CD4+ and CD8+ T cells recognize and respond to processed antigens associated with major histocompatibility complex-encoded molecules (MHC). It is during thymic development that selection processes act on immature CD4+CD8+ thymocytes to ensure the fonnation of a repertoire of functional T cells1,2. Thus, immature T cells expressing an ∝β TCR with specificity for self-peptides plus MHC class I or class II molecules are positively selected, differentiating into CD8+ or CD4+ T cells, respectively3,4,5,6. Immature thymocytes lacking or expressing a non-selectable TCR undergo programmed cell death1. Additionally, those CD4+CD8+ T cells expressing an autospecific TCR may undergo programmed cell death 7,8 (negative selection). The CD4 and CD8 molecules are thought to actively participate in these T cell repertoire selection events through their coreceptor functions9. In a coreceptor model, the TCR and appropriate coreceptor molecule recognize and interact with the same MHC molecule, with CD4 or CD8 potentiating TCR-derived intracellular signals10,1l.12. Recent reports have demonstrated that mutations affecting CD8/class I MHC interactions disrupt both positive and negative selection in the thymus13,14.


Transgenic Mouse Negative Selection Protein Tyrosine Kinase Double Transgenic Mouse Thymocyte Development 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    H. von Boehmer, Developmental biology of T cells in T cell receptor transgenic mice, Ann. Rev. Immunol. 8:531 (1990).Google Scholar
  2. 2.
    M. Blackman, J. Kappler, and P. Marrack, The role of tile T cell receptor in positive and negative selection of developing T cells, Science 248:1335 (1990).Google Scholar
  3. 3.
    H-S. Teh, P. Kisielow, B. Scott, H. Kishi, Y. Uematsu, H. Bluthmann, and H. von Boehmer, Thymic major histocompatibility complex antigens and the all T-cell receptor determine the CD4/CD8 phenotype of T cells, Nature 335:229 (1988).Google Scholar
  4. 4.
    H. von Boehmer, and P. Kisielow, Self-nonself discrimination by T cells, Science 248:1369 (1990).Google Scholar
  5. 5.
    L.J. Berg. A.M. Pullen, B.F. de St. Groth, D. Mathis, C. Benoist, and M. Davis, Antigen/MHC specific T-cells are preferentially exported from the thymus in the presence of their MHC ligand, Cell 58:1035 (1989).Google Scholar
  6. 6.
    W.C. Sha, C.A. Nelson, R.D. Newberry, J.K. Pullen, L.R. Pease, J.H. Russell, and D.Y. Loh, Positive selection of transgenic-receptor bearing thymocytes by Kb antigen is altered by Kb mutations that involve peptide binding, Proc. Natl. Acad. Sci. 87:6186 (1990).Google Scholar
  7. 7.
    J.W. Kappler, N. Roehm, and P. Marrack, T cell tolerance by clonal elimination in the thymus, Cell 49:273 (1987).Google Scholar
  8. 8.
    P. Kisielow, H. Bluthman, U.D. Staerz, M. Steinmetz, and H. von Boehmer, Tolerance in T cell receptor transgenic mice involves deletion of non-mature CD4+cD8+ thymocytes, Nature 333:742 (1988).Google Scholar
  9. 9.
    C.A. Janeway, Jr., Accessories of coreceptors, Nature 335:208 (1988).Google Scholar
  10. 10.
    U. Diazani, A. Shaw, B.K. Al-Ramadi, R.T. Kubo, and C.A. Janeway, Jr., Physical association of CD4 with the T cell receptor, J. Immunol. 148:678 (1992).Google Scholar
  11. 11.
    R.D. Salter, R.J. Benjamin, P.K. Wesley, S.E. Buxton, T.P.J. Garrett, C. Clayberger, A.M. Krensky, A.M Norment, D.R. Littman, and P. Parham, A binding site for the T-cell coreceptor CD8 on the ∝3 domain of HLA-A2, Nature 345:41 (1990).Google Scholar
  12. 12.
    F. Emmrich, V. Strittmatter, and K. Eichmann, Cross-linking of the TCR complex with the subsetspecific differentiation antigen stimulates interleukin 2 receptor expression in human CD4 and CD8 T cells, Proc. Natl. Acad. Sci. 83:8298 (1986).Google Scholar
  13. 13.
    A.L. Ingold, C. Landel, C. Knall, G.A. Evans, and T. Potter, Co-engagement of CD8 with the T cell receptor is required for negative selection, Nature 352:721 (1991).Google Scholar
  14. 14.
    C.I. Aldrich, R.E. Hammer, S. Jones-Youngblood, U. Koszinowski, L. Hood, I. Stoyonowski, and J. Forman, Negative and positive selection of antigen-specific cytotoxic T lymphocytes affected by the ∝3 domain of MHC c1asss I molecules. Nature 352:718 (1991).Google Scholar
  15. 15.
    A. Weiss, I. Imboden, K. Hardy, B. Manger, C. Terhorst, and I. Stobo, The role of the T3/antigen receptor complex in T cell activation, Ann. Rev. Immunol. 4:593 (1986).Google Scholar
  16. 16.
    M.P. Cooke, and R.M. Perlmutter, Expression of a novel form of the fyn proto-oncogene in hematopoeitic cells, New Biologist 1:66 (1989).Google Scholar
  17. 17.
    L.E. Samelson, A.F. Phillips, E.T. Luong, and R.D. Klausner, Association of the fyn protein tyrosine kinase with the T cell antigen receptor, Proc. Natl. Acad. Sci. 87:4358 (1990).Google Scholar
  18. 18.
    M.P. Cooke, K.M. Abraham, K.A. Forbush, and R.M. Perlmutter, Regulation of T cell receptor signalling by a src family protein tyrosine kinase (p59fyn), Cell 65:281 (1991).Google Scholar
  19. 19.
    C.E. Rudd, J.M. Trevillyan, J.D. Dasgupta, L.W. Wong, and S.F. Schlossman, The CD4 receptor is complexed in detergent lysates to a protein tyrosine kinase (pp58) from human T lymphocytes, Proc. Natl. Acad. Sci. 85:5190 (1988).Google Scholar
  20. 20.
    A. Veillette, M.A. Bookman, E.M. Horak, and I.B. Bolen, The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck, Cell 55:301 (1988).Google Scholar
  21. 21.
    A. Veillette, J.C. Zuniga-Pflucker, J.B. Bolen, and A.M. Kruisbeek, Engagment of CD4 and CD8 expressed on immature thymocytes induces activation of intracellular tyrosine phosphorylation pathways, J. Exp. Med. 170:1671 (1989).Google Scholar
  22. 22.
    L.K. Gilliland, H.-S. Teh, F.M. Uckun, N.A. Norris, S.-I. Teh, G.L. Schieven, and I.A. Ledbetter, CD4 and CD8 are positive regulators of T cell receptor signal transduction in early T cell differentation, J. Immunol. 146:1759 (1991).Google Scholar
  23. 23.
    K.M. Abraham, S.D. Levin, J.D. Marth, K.A. Forbush, and R.M. Perlmutter, Delayed thymocyte development induced by augmented expression of p56lck, J. Exp. Med. 173:1421 (1991).Google Scholar
  24. 24.
    H.-S. Teh, A.M. Garvin, K.A. Forbush, D.A. Carlow, C.B. Davis, D.R. Littman, and R.M. Perlmutter, Participation of CD4 coreceptor molecules in T cell repertoire selection, Nature 349:241 (1991).Google Scholar
  25. 25.
    N.S.C. van Oers, A.M. Garvin, C.B. Davis, K.A. Forbush, D.A. Carlow, D.R. Littman, R.M. Perlmutter, and H.-S. Teh, Disruption of CD8-dependent negative and positive selection of thymocytes is correlated with a decreased association between CD8 and the protein tyrosine kinase, p56lck, Eur. J. Immunol. In Press(1992).Google Scholar
  26. 26.
    U. Staerz, H. Rammensee, I. Benedetto, and M. Bevan, Characterization of a murine monoclonal antibody specific for an allotypic determinant on T cell antigen receptor, J. Immunol. 134:3994 (1985).Google Scholar
  27. 27.
    A.S. Shaw, K.E. Amrein, C. Hammond, D.F. Stem, B.M. Sefton, and I.K. Rose, The lck tyrosine protein kinase interacts with the cytoplasmic tail of the CD4 glycoprotein through its unique amino-terminal domain, Cell 59:627 (1989).Google Scholar
  28. 28.
    I.M. Turner, M.H. Brodsky, B.A. Irving, S.D. Levin, R.M. Perlmutter, and D.R. Littman, Interaction of the unique N-terminal region of tyrosine kinase p56lck with cytoplasmic domains of CD4 and CD8 is mediated by cysteine motifs, Cell 60:755 (1990).Google Scholar
  29. 29.
    D.A. Carlow, N.S.C. van Oers, S.-J. Teh, and H.-S. Teh, Deletion of antigen-specific immature thymocytes by dendritic cells requires LFA-1/1CAM interaction, J. Immunol. In Press (1992).Google Scholar
  30. 30.
    H.-S. Teh, H. Kishi, B. Scott, P. Borgulya, H. von Boehmer, and P. Kisielow, Early deletion and late positive selection of T cells expressing a male-specific receptor in T-cell receptor transgenic mice, Develop. Immunol. 1:1 (1990).Google Scholar
  31. 31.
    A. Chan, B.A. Irving, J.D. Fraser, and A. Weiss, The ζ chain is associated with a tyrosine kinase and upon T-cell antigen receptor stimulation associates with ZAP-70, a 70-kDa tyrosine phosphoprotein, Proc. Natl. Acad. Sci. 88:9166 (1991).Google Scholar
  32. 32.
    F. Letourneur, and R.D. Klausner, Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3-ε, Science 255:79 (1992).Google Scholar
  33. 33.
    A.-M.K. Wegener, F. Letourner, A. Hoeveler, T. Brocker, F. Luton, and B. Malissen, The T cell receptor/CD3 complex is composed of at least two autonomous transduction modules, Cell 68:83 (1992).Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Nicolai S. C. van Oers
    • 1
  • Alex M. Garvin
    • 2
  • Michael P. Cooke
    • 3
  • Craig B. Davis
    • 4
  • D. R. Littman
    • 4
  • Roger M. Perlmutter
    • 3
  • Hung-Sia Teh
    • 1
  1. 1.Department of MicrobiologyUniversity of British ColumbiaVancouverCanada
  2. 2.CIMLMarseille, Cedex 9France
  3. 3.Departments of Immunology, Biochemistry, and Medicine (Medical Genetics), and the Howard Hughes Medical InstituteUniversity of WashingtonSeattleUSA
  4. 4.Howard Hughes Medical Institute, Department of Microbiology and ImmunologyUniversity of California, San FranciscoSan FranciscoUSA

Personalised recommendations