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.

  • Article
  • Published:

The inter-relatedness and interdependence of mouse T cell receptor γδ+ and αβ+ cells

Nature Immunology volume 4, pages 991–998 (2003)Cite this article

Abstract

Although T cell receptor (TCR)γδ+ and TCRαβ+ cells are commonly viewed as functionally independent, their relatedness and potential interdependence remain enigmatic. Here we have identified a gene profile that distinguishes mouse γδ cell populations from conventional αβ T cells. However, this profile was also expressed by sets of unconventional αβ T cells. Therefore, whereas TCR specificity determines the involvement of a T cell in an immune response, the cell's functional potential, as assessed by gene expression, does not segregate with the TCR. By monitoring the described gene profile, we show that γδ T cell development and function in TCRβ-deficient mice was impaired because of the absence of αβ T cell progenitors. Thus, normal γδ cell development is dependent on the development of conventional αβ T cells.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: RDA identifies ICER as a marker of TCRγδ+ cells.
Figure 2: ICER expression does not segregate with TCR isotype.
Figure 3: Expression profiling of intestinal IEL subsets.
Figure 4: Gene expression does not segregate with TCR isotype.
Figure 5: Resting γδ cells from TCRβ-deficient mice show an abnormal pattern of gene and protein expression.
Figure 6: Impaired physiology of activated splenic γδ cells from TCRβ-deficient mice.
Figure 7: Double-positive thymocytes promote ICER expression in thymic γδ cells.

Similar content being viewed by others

References

  1. Raulet, D.H. The structure, function, and molecular genetics of the γδ T cell receptor. Annu. Rev. Immunol. 7, 175–207 (1989).

    Article  CAS  Google Scholar 

  2. Haas, W., Pereira, P. & Tonegawa, S. γδ cells. Annu. Rev. Immunol. 11, 637–685 (1993).

    Article  CAS  Google Scholar 

  3. Born, W. et al. Immunoregulatory functions of γδ T cells. Adv. Immunol. 71, 77–144 (1999).

    Article  CAS  Google Scholar 

  4. Hayday, A.C. γδ cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18, 975–1026 (2000).

    Article  CAS  Google Scholar 

  5. Chien, Y.H., Jores, R. & Crowley, M.P. Recognition by γδ T cells. Annu. Rev. Immunol. 14, 511–532 (1996).

    Article  CAS  Google Scholar 

  6. Mombaerts, P., Arnoldi, J., Russ, F., Tonegawa, S. & Kaufmann, S.H. Different roles of αβ and γδ T cells in immunity against an intracellular bacterial pathogen. Nature 365, 53–56 (1993).

    Article  CAS  Google Scholar 

  7. Girardi, M. et al. Regulation of cutaneous malignancy by γδ T cells. Science 294, 605–609 (2001).

    Article  CAS  Google Scholar 

  8. Jameson, J. et al. A role for skin γδ T cells in wound repair. Science 296, 747–749 (2002).

    Article  CAS  Google Scholar 

  9. Mukasa, A. et al. Bacterial infection of the testis leading to autoaggressive immunity triggers apparently opposed responses of αβ and γδ T cells. J. Immunol. 155, 2047–2056 (1995).

    CAS  PubMed  Google Scholar 

  10. Roberts, S.J. et al. T-cell αβ and γδ deficient mice display abnormal but distinct phenotypes toward a natural, widespread infection of the intestinal epithelium. Proc. Natl. Acad. Sci. USA 93, 11774–11779 (1996).

    Article  CAS  Google Scholar 

  11. Girardi, M. et al. Resident skin-specific γδ T cells provide local, nonredundant regulation of cutaneous inflammation. J. Exp. Med. 195, 855–867 (2002).

    Article  CAS  Google Scholar 

  12. Bucy, R.P., Chen, C.L., Cihak, J., Losch, U. & Cooper, M.D. Avian T cells expressing γδ receptors localize in the splenic sinusoids and the intestinal epithelium. J. Immunol. 141, 2200–2205 (1988).

    CAS  PubMed  Google Scholar 

  13. Boismenu, R. & Havran, W.L. Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 266, 1253–1255 (1994).

    Article  CAS  Google Scholar 

  14. Fahrer, A.M. et al. Attributes of γδ intraepithelial lymphocytes as suggested by their transcriptional profile. Proc. Natl. Acad. Sci. USA 98, 10261–10266 (2001).

    Article  CAS  Google Scholar 

  15. Shires, J., Theodoridis, E. & Hayday, A.C. Biological insights into TCRγδ+ and TCRαβ+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).

    Article  CAS  Google Scholar 

  16. Hubank, M. & Schatz, D.G. Identifying differences in mRNA expression by representational difference analysis of cDNA. Nucleic Acids Res. 22, 5640–5648 (1994).

    Article  CAS  Google Scholar 

  17. Petrie, H.T., Scollay, R. & Shortman, K. Commitment to the T cell receptor-αβ or -γδ lineages can occur just prior to the onset of CD4 and CD8 expression among immature thymocytes. Eur. J. Immunol. 22, 2185–2188 (1992).

    Article  CAS  Google Scholar 

  18. Philpott, K.L. et al. Lymphoid development in mice congenitally lacking T cell receptor αβ-expressing cells. Science 256, 1448–1452 (1992).

    Article  CAS  Google Scholar 

  19. Kehrl, J.H. & Sinnarajah, S. RGS2: a multifunctional regulator of G-protein signaling. Int. J. Biochem. Cell. Biol. 34, 432–438 (2002).

    Article  CAS  Google Scholar 

  20. He, Y.W. Orphan nuclear receptors in T lymphocyte development. J. Leukoc. Biol. 72, 440–446 (2002).

    CAS  PubMed  Google Scholar 

  21. Sassone-Corsi, P. Goals for signal transduction pathways: linking up with transcriptional regulation. EMBO J. 13, 4717–4728 (1994).

    Article  CAS  Google Scholar 

  22. Bruno, L., Fehling, H.J. & von Boehmer, H. The αβ T cell receptor can replace the γδ receptor in the development of γδ lineage cells. Immunity 5, 343–352 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Passoni, L. et al. Intrathymic δ selection events in γδ cell development. Immunity 7, 83–95 (1997).

    Article  CAS  Google Scholar 

  25. Jarry, A., Cerf-Bensussan, N., Brousse, N., Selz, F. & Guy-Grand, D. Subsets of CD3+ (T cell receptor αβ or γδ) and CD3− lymphocytes isolated from normal human gut epithelium display phenotypical features different from their counterparts in peripheral blood. Eur. J. Immunol. 20, 1097–1103 (1990).

    Article  CAS  Google Scholar 

  26. Lefrançois, L. Phenotypic complexity of intraepithelial lymphocytes of the small intestine. J. Immunol. 147, 1746–1751 (1991).

    PubMed  Google Scholar 

  27. Hayday, A., Theodoridis, E., Ramsburg, E. & Shires, J. Intraepithelial lymphocytes: exploring the Third Way in immunology. Nat. Immunol. 2, 997–1003 (2001).

    Article  CAS  Google Scholar 

  28. Arstila, T. et al. Identical T cell clones are located within the mouse gut epithelium and lamina propria and circulate in the thoracic duct lymph. J. Exp. Med. 191, 823–834 (2000).

    Article  CAS  Google Scholar 

  29. Eiseman, E. & Bolen, J.B. Engagement of the high-affinity IgE receptor activates src protein-related tyrosine kinases. Nature 355, 78–80 (1992).

    Article  CAS  Google Scholar 

  30. Heiken, H., Schulz, R.J., Ravetch, J.V., Reinherz, E.L. & Koyasu, S. T lymphocyte development in the absence of Fcε receptor Iγ subunit: analysis of thymic-dependent and independent αβ and γδ pathways. Eur. J. Immunol. 26, 1935–1943 (1996).

    Article  CAS  Google Scholar 

  31. Laky, K., Lefrancois, L. & Puddington, L. Age-dependent intestinal lymphoproliferative disorder due to stem cell factor receptor deficiency: parameters in small and large intestine. J. Immunol. 158, 1417–1427 (1997).

    CAS  PubMed  Google Scholar 

  32. Suzuki, H., Duncan, G.S., Takimoto, H. & Mak, T.W. Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor β chain. J. Exp. Med. 185, 499–505 (1997).

    Article  CAS  Google Scholar 

  33. Diefenbach, A. et al. Selective associations with signaling proteins determine stimulatory versus costimulatory activity of NKG2D. Nat. Immunol. 3, 1142–1149 (2002).

    Article  CAS  Google Scholar 

  34. Gilfillan, S., Ho, E.L., Cella, M., Yokoyama, W.M. & Colonna, M. NKG2D recruits two distinct adapters to trigger NK cell activation and costimulation. Nat. Immunol. 3, 1150–1155 (2002).

    Article  CAS  Google Scholar 

  35. Kohyama, M. et al. Cytolytic and IFN-γ-producing activities of γδ T cells in the mouse intestinal epithelium are T cell receptor-β-chain dependent. Proc. Natl. Acad. Sci. USA 96, 7451–7455 (1999).

    Article  CAS  Google Scholar 

  36. Fehling, H.J., Krotkova, A., Saint-Ruf, C. & von Boehmer, H. Crucial role of the pre-T-cell receptor a gene in development of αβ but not γδ T cells. Nature 375, 795–798 (1995).

    Article  CAS  Google Scholar 

  37. Wilson, A. & MacDonald, H.R. A limited role for β-selection during γδ T cell development. J. Immunol. 161, 5851–5854 (1998).

    CAS  PubMed  Google Scholar 

  38. Blendy, J.A., Kaestner, K.H., Weinbauer, G.F., Nieschlag, E. & Schutz, G. Severe impairment of spermatogenesis in mice lacking the CREM gene. Nature 380, 162–165 (1996).

    Article  CAS  Google Scholar 

  39. Havran, W.L. & Allison, J.P. Origin of Thy-1+ dendritic epidermal cells of adult mice from fetal thymic precursors. Nature 344, 68–70 (1990).

    Article  CAS  Google Scholar 

  40. Cerdan, C. et al. CD28 costimulation up-regulates long-term IL-2Rβ expression in human T cells through combined transcriptional and post-transcriptional regulation. J. Immunol. 154, 1007–1013 (1995).

    CAS  PubMed  Google Scholar 

  41. Romero, P. et al. Expression of CD94 and NKG2 molecules on human CD4+ T cells in response to CD3-mediated stimulation. J. Leukoc. Biol. 70, 219–224 (2001).

    CAS  PubMed  Google Scholar 

  42. Poussier, P., Ning, T., Banerjee, D. & Julius, M. A unique subset of self-specific intraintestinal T cells maintains gut integrity. J. Exp. Med. 195, 1491–1497 (2002).

    Article  CAS  Google Scholar 

  43. Rabinowich, H. et al. Physical and functional association of Fcμ receptor on human natural killer cells with the ζ- and FcεRIγ-chains and with src family protein tyrosine kinases. J. Immunol. 157, 1485–1491 (1996).

    CAS  PubMed  Google Scholar 

  44. Bendelac, A. Positive selection of mouse NK1+ T cells by CD1-expressing cortical thymocytes. J. Exp. Med. 182, 2091–2096 (1995).

    Article  CAS  Google Scholar 

  45. Jenkinson, E.J., Anderson, G. & Owen, J.J. Studies on T cell maturation on defined thymic stromal cell populations in vitro. J. Exp. Med. 176, 845–853 (1992).

    Article  CAS  Google Scholar 

  46. Shen, Y. et al. Adaptive immune response of Vγ2Vδ2+ T cells during mycobacterial infections. Science 295, 2255–2258 (2002).

    Article  CAS  Google Scholar 

  47. Wen, L. et al. Primary γδ cell clones can be defined phenotypically and functionally as Th1/Th2 cells and illustrate the association of CD4 with Th2 differentiation. J. Immunol. 160, 1965–1974 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank M. Hubank, J. Dunne, G. Clark, W. Turnbull, D. Davies, A. Eddaoudi, C. Simpson, G. Barnes, C. Trigueros, J. Lewis, A. Denzel, S. Clarke, D. Oppenheim, V. Giuggio and S. Creighton for help; G. Schutz for ICER-lacZ mice; G. LeClercq for anti-Ly49E; and R. Ahmed for RNA from LCMV-specific T cells. We acknowledge a Wellcome Trust Programme Grant (A.C.H.) and the Fundação para a Ciência e Tecnologia (Portugal) through the Gulbenkian PhD Programme (B.S.-S.).

Author information

Author notes

  1. John Shires

    Present address: Department of Microbiology and Immunology, Emory University, Atlanta, Georgia, 30322, USA

  2. Michael J Owen

    Present address: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK

  3. Daniel J Pennington and Bruno Silva-Santos: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunobiology, Guy's King's Saint Thomas' Medical School, Guy's Hospital, London, SE1 9RT, UK

    Daniel J Pennington, Bruno Silva-Santos, John Shires, Efstathios Theodoridis, Christopher Pollitt, Emma L Wise & Adrian C Hayday

  2. Department of Dermatology and Section of Immunobiology, Yale University, New Haven, 06511, Connecticut, USA

    Robert E Tigelaar

Authors
  1. Daniel J Pennington
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Silva-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John Shires
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Efstathios Theodoridis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christopher Pollitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Emma L Wise
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert E Tigelaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Adrian C Hayday
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Adrian C Hayday.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pennington, D., Silva-Santos, B., Shires, J. et al. The inter-relatedness and interdependence of mouse T cell receptor γδ+ and αβ+ cells. Nat Immunol 4, 991–998 (2003). https://doi.org/10.1038/ni979

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni979

This article is cited by

Search

Advanced 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