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:

LAT regulates γδ T cell homeostasis and differentiation

Abstract

LAT (linker for activation of T cells) is essential for T cell receptor signaling. Mice homozygous for a mutation of the three C-terminal LAT tyrosine residues showed a block in αβ T cell development and a partially impaired γδ T cell development. Without intentional immunization, they accumulated γδ T cells in the spleen and lymph nodes that chronically produced T helper type 2 cytokines in large amounts, and caused the maturation of plasma cells secreting immunoglobulin E (IgE) and IgG1. These effects are very similar to that triggered in the αβ lineage by a mutation involving a distinct LAT tyrosine. Thus, LAT is an essential regulator of T cell homeostasis and terminal differentiation.

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: Impeded T cell development in LatY7/8/9F mice.
Figure 2: TCRγδ+ and CD3+ cells developing in LatY7/8/9F thymi differ from those in wild-type thymi.
Figure 3: A CD5+CD90.2+ population expands over time in the spleens and lymph nodes of LatY7/8/9F mice.
Figure 4: Phenotype of T cells bearing γδ TCR and accumulating in secondary lymphoid organs of LatY7/8/9F mice.
Figure 5: Vγ and Vδ usage in TCRγδ+ cells expressing wild-type LAT or LATY7/8/9F molecules.
Figure 6: Histological and immunohistochemical analyses of LatY7/8/9F spleens.
Figure 7: TH2 cytokine production in T cells freshly isolated from peripheral lymphoid organs from LatY7/8/9F, LatY6F and Eβ-deficient mice.
Figure 8: Hyperactivated B lymphocytes and serum concentrations of IgG1 and IgE antibodies in unimmunized LAT mutant mice.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Malissen, B., Ardouin, L., Lin, S.Y., Gillet, A. & Malissen, M. Function of the CD3 subunits of the pre-TCR and TCR complexes during T cell development. Adv. Immunol. 72, 103–148 (1999).

    Article  CAS  Google Scholar 

  2. Von Boehmer, H. et al. Thymic selection revisited: how essential is it? Immunol. Rev. 191, 62–78 (2003).

    Article  CAS  Google Scholar 

  3. Wilson, A., Capone, M. & MacDonald, H.R. Unexpectedly late expression of intracellular CD3ε and TCRγδ proteins during adult thymus development. Int. Immunol. 11, 1641–1650 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Ferrero, I., Wilson, A., Beermann, F., Held, W. & MacDonald, H.R. T cell receptor specificity is critical for the development of epidermal γδ T cells. J. Exp. Med. 194, 1473–1483 (2001).

    Article  CAS  Google Scholar 

  6. Jordan, M.S., Singer, A.L. & Koretzky, G.A. Adaptors as central mediators of signal transduction in immune cells. Nat. Immunol. 4, 110–116 (2003).

    Article  CAS  Google Scholar 

  7. Lin, J. & Weiss, A. Identification of the minimal tyrosine residues required for linker for activation of T cell function. J. Biol. Chem. 276, 29588–29595 (2001).

    Article  CAS  Google Scholar 

  8. Paz, P.E. et al. Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells. Biochem. J. 356, 461–471 (2001).

    Article  CAS  Google Scholar 

  9. Zhang, W. et al. Association of Grb2, Gads, and phospholipase C-γ 1 with phosphorylated LAT tyrosine residues. Effect of LAT tyrosine mutations on T cell antigen receptor-mediated signaling. J. Biol. Chem. 275, 23355–23361 (2000).

    Article  CAS  Google Scholar 

  10. Zhu, M., Janssen, E. & Zhang, W. Minimal requirement of tyrosine residues of linker for activation of T cells in TCR signaling and thymocyte development. J. Immunol. 170, 325–333 (2003).

    Article  CAS  Google Scholar 

  11. Hartgroves, L.C. et al. Synergistic assembly of linker for activation of T cells signaling protein complexes in T cell plasma membrane domains. J. Biol. Chem. 278, 20389–20394 (2003).

    Article  CAS  Google Scholar 

  12. Yablonski, D., Kadlecek, T. & Weiss, A. Identification of a phospholipase C-γ1 (PLC-γ1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-γ1 and NFAT. Mol. Cell. Biol. 21, 4208–4218 (2001).

    Article  CAS  Google Scholar 

  13. Zhang, W. et al. Essential role of LAT in T cell development. Immunity 10, 323–332 (1999).

    Article  CAS  Google Scholar 

  14. Sommers, C.L. et al. Knock-in mutation of the distal four tyrosines of linker for activation of T cells blocks murine T cell development. J. Exp. Med. 194, 135–142 (2001).

    Article  CAS  Google Scholar 

  15. Sommers, C.L. et al. A LAT mutation that inhibits T cell development yet induces lymphoproliferation. Science 296, 2040–2043 (2002).

    Article  CAS  Google Scholar 

  16. Aguado, E. et al. Induction of T helper type 2 immunity by a point mutation in the LAT adaptor. Science 296, 2036–2040 (2002).

    Article  CAS  Google Scholar 

  17. Pivniouk, V. et al. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76. Cell 94, 229–238 (1998).

    Article  CAS  Google Scholar 

  18. Zorbas, M. & Scollay, R. Development of γδ T cells in the adult murine thymus. Eur. J. Immunol. 23, 1655–1660 (1993).

    Article  CAS  Google Scholar 

  19. 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 

  20. Leduc, I. et al. T cell development in TCRβ enhancer-deleted mice: implications for αβ T cell lineage commitment and differentiation. J. Immunol. 165, 1364–1673 (2000).

    Article  CAS  Google Scholar 

  21. Pereira, P., Gerber, D., Huang, S.Y. & Tonegawa, S. Ontogenic development and tissue distribution of Vγ1-expressing γδ T lymphocytes in normal mice. J. Exp. Med. 182, 1921–1930 (1995).

    Article  CAS  Google Scholar 

  22. Hayes, S.M. & Love, P.E. Distinct structure and signaling potential of the γδ TCR complex. Immunity 16, 827–838 (2002).

    Article  CAS  Google Scholar 

  23. Kadlecek, T.A. et al. Differential requirements for ZAP-70 in TCR signaling and T cell development. J. Immunol. 161, 4688–4694 (1998).

    CAS  Google Scholar 

  24. Swat, W. et al. Essential role for Vav1 in activation, but not development, of γδ T cells. Int. Immunol. 15, 215–221 (2003).

    Article  CAS  Google Scholar 

  25. Jaffe, S., Harris, N.L., Stein, H. & Vardiman, J.W. World Health Organization Classifiaction of Tumors. Pathology and Genetics of Tumours of Hematopoietic and Lymphoid Tissues (IARC Press, Lyon, 2001).

    Google Scholar 

  26. Morse, H.C., 3rd . et al. Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 100, 246–258 (2002).

    Article  CAS  Google Scholar 

  27. Arnulf, B. et al. Nonhepatosplenic γδ T-cell lymphoma: a subset of cytotoxic lymphomas with mucosal or skin localization. Blood 91, 1723–1731 (1998).

    CAS  PubMed  Google Scholar 

  28. Ferrick, D.A. et al. Differential production of interferon-γ and interleukin-4 in response to Th1- and Th2-stimulating pathogens by γδ T cells in vivo. Nature 373, 255–257 (1995).

    Article  CAS  Google Scholar 

  29. 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 

  30. Murphy, K.M. & Reiner, S.L. The lineage decisions of helper T cells. Nat. Rev. Immunol. 2, 933–944 (2002).

    Article  CAS  Google Scholar 

  31. Grogan, J.L. & Locksley, R.M. T helper cell differentiation: on again, off again. Curr. Opin. Immunol. 14, 366–372 (2002).

    Article  CAS  Google Scholar 

  32. Ho, I.C. & Glimcher, L.H. Transcription: tantalizing times for T cells. Cell 109, S109–120 (2002).

    Article  CAS  Google Scholar 

  33. Yin, Z. et al. Dominance of IL-12 over IL-4 in γδ T cell differentiation leads to default production of IFN-γ: failure to down-regulate IL-12 receptor β2-chain expression. J. Immunol. 164, 3056–3064 (2000).

    Article  CAS  Google Scholar 

  34. Yin, Z. et al. T-Bet expression and failure of GATA-3 cross-regulation lead to default production of IFN-γ by γδ T cells. J. Immunol. 168, 1566–1571 (2002).

    Article  CAS  Google Scholar 

  35. Egan, P.J. & Carding, S.R. Downmodulation of the inflammatory response to bacterial infection by γδ T cells cytotoxic for activated macrophages. J. Exp. Med. 191, 2145–2158 (2000).

    Article  CAS  Google Scholar 

  36. Azuara, V., Levraud, J.P., Lembezat, M.P. & Pereira, P. A novel subset of adult γδ thymocytes that secretes a distinct pattern of cytokines and expresses a very restricted T cell receptor repertoire. Eur. J. Immunol. 27, 544–553 (1997).

    Article  CAS  Google Scholar 

  37. Wen, L. et al. Germinal center formation, immunoglobulin class switching, and autoantibody production driven by “non α/β” T cells. J. Exp. Med. 183, 2271–2282 (1996).

    Article  CAS  Google Scholar 

  38. Bhan, A.K., Mizoguchi, E., Smith, R.N. & Mizoguchi, A. Spontaneous chronic colitis in TCRα-mutant mice; an experimental model of human ulcerative colitis. Int. Rev. Immunol. 19, 123–138 (2000).

    Article  CAS  Google Scholar 

  39. Munk, M.E., Fazioli, R.A., Calich, V.L. & Kaufmann, S.H. Paracoccidioides brasiliensis-stimulated human γδ T cells support antibody production by B cells. Infect. Immun. 63, 1608–1610 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Horner, A.A., Jabara, H., Ramesh, N. & Geha, R.S. γδ T lymphocytes express CD40 ligand and induce isotype switching in B lymphocytes. J. Exp. Med. 181, 1239–1244 (1995).

    Article  CAS  Google Scholar 

  41. Yamasaki, S. et al. Gads/Grb2-mediated association with LAT is critical for the inhibitory function of Gab2 in T cells. Mol. Cell. Biol. 23, 2515–2529 (2003).

    Article  CAS  Google Scholar 

  42. Sallusto, F. & Lanzavecchia, A. The instructive role of dendritic cells on T-cell responses. Arthritis Res. 4, S127–132 (2002).

    Article  Google Scholar 

  43. Rogers, P.R. & Croft, M. CD28, Ox-40, LFA-1, and CD4 modulation of Th1/Th2 differentiation is directly dependent on the dose of antigen. J. Immunol. 164, 2955–2963 (2000).

    Article  CAS  Google Scholar 

  44. Jorritsma, P.J., Brogdon, J.L. & Bottomly, K. Role of TCR-induced extracellular signal-regulated kinase activation in the regulation of early IL-4 expression in naive CD4+ T cells. J. Immunol. 170, 2427–2434 (2003).

    Article  CAS  Google Scholar 

  45. Boonstra, A. et al. Flexibility of mouse classical and plasmacytoid-derived dendritic cells in directing T helper type 1 and 2 cell development: dependency on antigen dose and differential toll-like receptor ligation. J. Exp. Med. 197, 101–109 (2003).

    Article  CAS  Google Scholar 

  46. Spanopoulou, E. et al. Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. Genes Dev. 8, 1030–1042 (1994).

    Article  CAS  Google Scholar 

  47. Kress, C., Vandormael-Pournin, S., Baldacci, P., Cohen-Tannoudji, M. & Babinet, C. Nonpermissiveness for mouse embryonic stem (ES) cell derivation circumvented by a single backcross to 129/Sv strain: establishment of ES cell lines bearing the Omd conditional lethal mutation. Mamm. Genome 9, 998–1001 (1998).

    Article  CAS  Google Scholar 

  48. Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995).

    Article  CAS  Google Scholar 

  49. Pannetier, C., Even, J. & Kourilsky, P. T-cell repertoire diversity and clonal expansions in normal and clinical samples. Immunol. Today 16, 176–181 (1995).

    Article  CAS  Google Scholar 

  50. Perron, H. et al. Multiple sclerosis retrovirus particles and recombinant envelope trigger an abnormal immune response in vitro, by inducing polyclonal Vβ16 T-lymphocyte activation. Virology 287, 321–332 (2001).

    Article  CAS  Google Scholar 

  51. Garman, R.D., Doherty, P.J. & Raulet, D.H. Diversity, rearrangement, and expression of murine T cell γ genes. Cell 45, 733–742 (1986).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H.-T. He and X.J. Guo for assistance with immunoblotting; G. Delsol for discussion of histological analysis; A. Miazek, P. Golstein and L. Leserman for review of the manuscript; A. Gillet, N. Brun, M. Barad and E. Borel for advice; and A. Perry for editing the manuscript. Supported by Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique and specific grants from Association pour la Recherche sur le Cancer (ARECA), Association Française contre les Myopathies, European Communities (project QLG1-CT1999-00202). European Communities (to E.A.) and Fondation pour la Recherche Médicale (to E.A.) and Socièté Française d'Exportation des Ressources Educatives-CONACYT (to S.N.C.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bernard Malissen.

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

Nuñez-Cruz, S., Aguado, E., Richelme, S. et al. LAT regulates γδ T cell homeostasis and differentiation. Nat Immunol 4, 999–1008 (2003). https://doi.org/10.1038/ni977

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni977

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