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.

  • Letter
  • Published:

Csk controls antigen receptor-mediated development and selection of T-lineage cells

Abstract

The development and function of αβT lymphocytes depend on signals derived from pre-T and αβT cell receptors (preTCR and αβTCR) (reviewed in refs 1, 2). The engagement of these receptors leads to the activation of Lck and Fyn3,4, which are protein tyrosine kinases (PTKs) of the Src family. It remains unclear to what extent the activation of Src-family PTKs can direct the differentiation steps triggered by preTCR and αβTCR. Here we show that the inactivation of the negative regulator of Src-family PTKs, carboxy-terminal Src kinase (Csk)5, in immature thymocytes abrogates the requirement for preTCR, αβTCR and major histocompatibility complex (MHC) class II for the development of CD4+8+ double-positive and CD4+ single-positive thymocytes as well as peripheral CD4 αβT-lineage cells. These data show that Csk and its substrates are required to establish preTCR/αβTCR-mediated control over the development of αβT cells.

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: Conditional inactivation of csk results in the appearance of CD3CD4lo peripheral cells.
Figure 2: αβTCR-independent development of Csk-deficient T-lineage cells.
Figure 3: MHC class II- and αβTCR-independent development of Csk-deficient T-lineage cells.
Figure 4: Functional properties of Csk-deficient αβT-lineage cells.

Similar content being viewed by others

References

  1. von Boehmer, H. & Fehling, H. J. Structure and function of the pre-T cell receptor. Annu. Rev. Immunol. 15, 432–452 (1997).

    Article  Google Scholar 

  2. Mombaerts, P. Lymphocyte development and function in T-cell receptor and RAG-1 mutant mice. Int. Rev. Immunol. 13, 43–63 (1995).

    Article  CAS  Google Scholar 

  3. Alberola-Ila, J., Takaki, S., Kerner, J. D. & Perlmutter, R. M. Differential signaling by lymphocyte antigen receptors. Annu. Rev. Immunol. 15, 125–154 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Nada, S., Okada, M., MacAuley, A., Cooper, J. A. & Nakagawa, H. Cloning of a complementary DNA for a protein-tyrosine kinase that specifically phosphorylates a negative regulatory site of p60c-src. Nature 351, 69–72 (1991).

    Article  ADS  CAS  Google Scholar 

  6. Jameson, S. C., Hogquist, K. A. & Bevan, M. J. Positive selection of thymocytes. Annu. Rev. Immunol. 13, 93–126 (1995).

    Article  CAS  Google Scholar 

  7. Groves, T. et al. Fyn can partially substitute for Lck in T lymphocyte development. Immunity 5, 417–428 (1996).

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Mombaerts, P., Anderson, S. J., Perlmutter, R. M., Mak, T. W. & Tonegawa, S. An activated lck transgene promotes thymocyte development in RAG-1 mutant mice. Immunity 1, 261–267 (1994).

    Article  CAS  Google Scholar 

  10. Nada, S. et al. Constitutive activation of Src family kinases in mouse embryos that lack Csk. Cell 73, 1125–1135 (1993).

    Article  CAS  Google Scholar 

  11. Imamoto, A. & Soriano, P. Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice. Cell 73, 1117–1124 (1993).

    Article  CAS  Google Scholar 

  12. Hanks, S. K. & Hunter, T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structure and classification. FASEB J. 9, 576–596 (1995).

    Article  CAS  Google Scholar 

  13. Kühn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    Article  ADS  Google Scholar 

  14. Moore, T. A., von Freeden-Jeffry, U., Murray, R. & Zlotnik, A. Inhibition of gamma delta T cell development and early thymocyte maturation in IL-7−/− mice. J. Immunol. 157, 2366–2373 (1996).

    CAS  PubMed  Google Scholar 

  15. Mombaerts, P. et al. Mutations in T-cell antigen receptor genes α and β and block thymocyte development at different stages. Nature 360, 225–231 (1992).

    Article  ADS  CAS  Google Scholar 

  16. Wilson, A., Day, L. M., Scollay, R. & Shortman, K. Subpopulations of mature murine thymocytes: properties of CD4CD8+ and CD4+CD8 thymocytes lacking the heat-stable antigen. Cell Immunol. 117, 312–326 (1988).

    Article  CAS  Google Scholar 

  17. Swat, W., Dessing, M., von Boehmer, H. & Kisielow, P. CD69 expression during selection and maturation of CD4+8+ thymocytes. Eur. J. Immunol. 23, 739–746 (1993).

    Article  CAS  Google Scholar 

  18. Sprent, J. & Tough, D. F. Lymphocyte life-span and memory. Science 265, 1395–1400 (1994).

    Article  ADS  CAS  Google Scholar 

  19. Veillette, A., Bookman, M. A., Horak, E. M. & Bolen, J. B. The CD4 and CD8 T cell surface antigens are associated with the internal membrane tyrosine-protein kinase p56lck. Cell 55, 301–308 (1988).

    Article  CAS  Google Scholar 

  20. Norment, A. M., Forbush, K. A., Nguyen, N., Malissen, M. & Perlmutter, R. M. Replacement of pre-T cell recpetor signaling functions by the CD4 coreceptor. J. Exp. Med. 185, 121–130 (1997).

    Article  CAS  Google Scholar 

  21. Köntgen, F., Suss, G., Stewart, C., Steinmetz, M. & Bluethmann, H. Targeted disruption of the MHC class II Aα gene iC57BL/6 mice. Int. Immunol. 5, 957–964 (1993).

    Article  Google Scholar 

  22. Grusby, M. J., Johnson, R. S., Papaioannou, V. E. & Glimcher, L. H. Depletion of CD+ T cells in major histocompatibility complex class II-deficient mice. Science 253, 1417–1420 (1991).

    Article  ADS  CAS  Google Scholar 

  23. Gosgrove, D. et al. Mice lacking MHC class II molecules. Cell 66, 1051–1066 (1991).

    Article  Google Scholar 

  24. Torres, R. & Kühn, R. Laboratory Protocols for Conditional Gene Targeting (Oxford Univ. Press, (1997)).

  25. Ledbetter, J. A. & Herzenberg, L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol. Rev. 47, 63–90 (1979).

    Article  CAS  Google Scholar 

  26. Anderson, S. J., Abraham, K. M., Nakayama, T., Singer, A. & Perlmutter, R. M. Inhibiton of T-cell receptor β-chain gene rearrangement by overexpression of the non-receptor protein tyrosine kianse p56lck. EMBO J. 11, 4877–4886 (1992).

    Article  CAS  Google Scholar 

  27. Krotkova, A., von Boehmer, H. & Fehling, H. J. Allelic exclusion in pTα-deficient mice: no evidence for cell surface expression of two T cell receptor (TCR)-β chains but less efficient inhibition of endogeneous Vβ → (D)Jβ rearrangements in the presence of a functional TCR-β transgene. J. Exp. Med. 186, 767–775 (1997).

    Article  CAS  Google Scholar 

  28. Saijo, K., Park, S. Y., Ishida, Y., Arase, H. & Saito, T. Crucial role of Jak3 in negative selection of self-reactive T cells. J. Exp. Med. 185, 351–356 (1997).

    Article  CAS  Google Scholar 

  29. Murphy, E. et al. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J. Exp. Med. 183, 901–913 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A. Berns and H. Jacobs for TCRβ−/− mice; H. Bluethmann and I. Förster for Aα−/− mice; D. Loh and M. Löhning for DO11.10 mice; C. Göttlinger, B. Meiners, S. Irlenbusch and C.Uthoff-Hachenberg for technical assistance; and J. Howard and K. Rajewsky for discussions and critical reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft through SFB 243. C.S. was supported by the Fonds der Chemie. K.S. was supported by an EMBO long-term fellowship.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christian Schmedt.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmedt, C., Saijo, K., Niidome, T. et al. Csk controls antigen receptor-mediated development and selection of T-lineage cells. Nature 394, 901–904 (1998). https://doi.org/10.1038/29802

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/29802

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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