Abstract
Thymocytes from mice lacking the CD3δ chain of the T-cell receptor (TCR), unlike those of other CD3-deficient mice1,2, progress from a CD4-CD8- double-negative to a CD4+CD8+ double-positive stage. However, CD3δ-/- double-positive cells fail to undergo positive selection, by which double-positive cells differentiate into more mature thymocytes3. Positive selection is also impaired in mice expressing inactive components of the Ras/mitogen activated protein (MAP) kinase signalling pathway4,5,6. Here we show that CD3δ-/- thymocytes are defective in the induction of extracellular signal-regulated protein kinase (ERK) MAP kinases upon TCR engagement, whereas activation of other MAP kinases is unaffected. The requirement for CD3δ maps to its extracellular or transmembrane domains, or both, as expression of a tail-less CD3δ rescues both ERK activation and positive selection in CD3δ-/- mice. Furthermore, the defect correlates with severely impaired tyrosine phosphorylation of the linker protein LAT, and of the CD3ζ chain that is localized to membrane lipid rafts upon TCR engagement. Our data indicate that the blockade of positive selection of CD3δ-/- thymocytes may derive from defective tyrosine phosphorylation of CD3ζ in lipid rafts, resulting in impaired activation of the LAT/Ras/ERK pathway.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Malissen, M. et al. Altered T cell development in mice with a targeted mutation of the CD3-ε gene. EMBO J. 14, 4641 –4653 (1995).
Haks, M. C., Krimpenfort, P., Borst, J. & Kruisbeek, A. M. The CD3γ chain is essential for developmemt of both the TCRαβ and TCRγδ lineages. EMBO J. 17, 1871–1882 (1998).
Dave, V. P. et al. CD3δ deficiency arrest development of the αβ but not the γδ T cell lineage. EMBO J. 16, 1360–1370 (1997).
Swan, K. A. et al. Involvement of p21ras distinguishes positive and negative selection in thymocytes. EMBO J. 14, 276 –285 (1995).
O'Shea C. C., Crompton T., Rosewell, I. A., Hayday, A. C. & Owen, M. J. Raf regulates positive selection. Eur. J. Immunol. 26, 2350–2355 (1996).
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 ).
Dave, V. P., Zdancewicz, M. & Kappes, D. J. CD4 and CD8 T cell lineages show differential sensitivity to alterations in surface density and composition of the TCR complex. Immunity (submitted).
Jameson, S. C., Hogquist, K. A. & Bevan, M. J. Positive selection of thymocytes. Annu. Rev. Immunol. 13, 93–126 (1995).
D'Ambrosio, D., Cantrell, D. A., Frati, L., Santoni, A. & Testi, R. Involvement of p21ras activation in T cell CD69 expression. Eur. J. Immunol. 24, 616–620 (1994).
Pagés, G. et al. Defective thymocyte maturation in p44 MAP kinase (ERK1) knockout mice. Science 286 1374– 1377 (1999).
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).
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).
Schaeffer, H. J. & Weber, M. J. Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol. Cell. Biol. 19, 2435–2444 (1999).
Rudd, C. E. Adaptors and molecular scaffolds in immune cell signalling. Cell 96, 5–8 (1999 ).
Clements, J. L. et al. Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development. Science 281, 416–419 (1998).
Zhang, W. et al. Essential role of LAT in T cell development. Immunity 10, 323–332 ( 1999).
Bustelo, X. R. Regulatory and signaling properties of the Vav family. Mol. Cell. Biol. 20, 1461–1477 ( 2000).
Finco, T. S., Kadlecek, T., Zhang, W., Samelson, L. E. & Weiss, A. LAT is required for TCR-mediated activation of PLCγ1 and the Ras pathway. Immunity 9, 617– 626 (1998).
Xavier, R., Brennan, T., Li, Q., McCormack, C. & Seed, B. Membrane compartmentation is required for efficient T cell activation. Immunity 8, 723– 732 (1998).
Montixi, C. et al. Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains. EMBO J. 17, 5334–5348 (1998).
Zhang, W., Trible, R. P. & Samelson, L. E. LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. Immunity 9, 239–246 (1998).
Kersh, E. N., Shaw, A. S., & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor ζ phosphorylation. Science 281, 572–575 (1998).
Neel, B. G. Role of phosphatases in lymphocyte activation. Curr. Opin. Immunol. 9, 405–420 ( 1997).
Bäckström, B. T., Müller, U. & Palmer, E. Positive selection through a motif in the αβ T cell receptor. Science 281, 835– 838 (1998).
Malissen, B., Ardouin, L., Lin, S., 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).
Sahuquillo, A. G., Roumier, A., Teixeiro, E., Bragado, R., & Alarcón, B. T cell receptor (TCR) engagement in apoptosis-defective, but interleukin 2(IL-2)-producing, T cells results in impaired ZAP70/CD3ζ association. J. Exp. Med. 187, 1179—1192 (1998).
Dave, V. P. et al. Altered functional responsiveness of thymocyte subsets from CD3δ-deficient mice to TCR-CD3 engagement. Int. Immunol. 10, 1481–1490 ( 1998).
Dutz, J. P., Ong, C. J., Marth, J., & Teh, H. S. Distinct differentiative stages of CD4+CD8+ thymocyte development defined by the lack of coreceptor binding in positive selection. J. Immunol. 154, 2588–2599 ( 1995).
Acknowledgements
We thank G. Koretzky and L. Samelson for antibodies; J. Millán for technical advice; J. Palacin, M. A. Bordallo, M. C. Moreno and M. Gómez for technical support; and M. Alonso and E. Bernstein for critically reading the manuscript. This work was supported by grants from Comisión Interministerial de Ciencia y Tecnología and Comunidad de Madrid. P.D. was supported by a Comunidad de Madrid fellowship and E.F. by a Ministerio de Educación fellowship. The Centro de Biología Molecular is in part supported by Fundación Ramón Areces.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Delgado, P., Fernández, E., Dave, V. et al. CD3δ couples T-cell receptor signalling to ERK activation and thymocyte positive selection. Nature 406, 426–430 (2000). https://doi.org/10.1038/35019102
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/35019102
This article is cited by
-
Molecular and genetic parameters defining T‐cell clonal selection
Immunology & Cell Biology (2011)
-
Non-redundant function of the MEK5–ERK5 pathway in thymocyte apoptosis
The EMBO Journal (2008)
-
Signaling by the kinase MINK is essential in the negative selection of autoreactive thymocytes
Nature Immunology (2005)
-
Severe combined immunodeficiency caused by a splicing abnormality of the CD3? gene
European Journal of Pediatrics (2005)
-
Knockout mice: a paradigm shift in modern immunology
Nature Reviews Immunology (2001)
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.
