Systems Biology of T Cell Activation

  • J. A. Lindquist
  • B. Schraven
Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2007/3)


T lymphocytes are central players in the adaptive immune response to pathogens. Cytotoxic T cells are able to identify and eliminate virally infected cells, while helper T cells support B lymphocyte-dependent antibody production as well as produce the cytokines that will determine whether a cell- or antibody-mediated immune response is required. The activation of T cells by pathogens is a complex process requiring multiple tightly regulated signaling pathways. Defects within this network, however, can cause severe and chronic disorders such as autoimmunity. Therefore, improving our understanding of how T cells discriminate between antigens and how these signals are organized to yield distinct immune responses is of importance as this may lead to the identification of novel drug targets and better therapeutic strategies.


Transmembrane Adaptor Modular Binding Domain Cell Activation Network 
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.



The authors would like to thank Luca Simeoni and Tilo Beyer for helpful discussion and apologize to those colleagues whose work we have not cited particularly with respect to the complexity of TCR signaling. This work was supported in part by grants from the German Research Society (DFG FOR521), the German Ministry of Education and Research (BMBF FORSYS program) and the Sachsen-Anhalt Ministry of Education (Research Focus Dynamic Systems).


  1. Brdicka T, Pavlistová D, Leo A, Bruyns E, Korínek V, Angelisová P, Scherer J, Shevchenko A, Hilgert I, Cerný J, Drbal K, Kuramitsu Y, Kornacker B, Horejsí V, Schraven B (2000) Phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG), a novel ubiquitously expressed transmembrane adaptor protein, binds the protein tyrosine kinase csk and is involved in regulation of T cell activation. J Exp Med 191:1591–1604PubMedCrossRefGoogle Scholar
  2. Buday L, Wunderlich L, Tamas P (2002) The Nck family of adapter proteins: regulators of actin cytoskeleton. Cell Signal 14:723–731PubMedCrossRefGoogle Scholar
  3. Bunnell SC, Singer AL, Hong DI, Jacque BH, Jordan MS, Seminario MC, Barr VA, Koretzky GA, Samelson LE (2006) Persistence of cooperatively stabilized signaling clusters drives T cell activation. Mol Cell Biol 26:7155–7166PubMedCrossRefGoogle Scholar
  4. Campi G, Varma R, Dustin ML (2005) Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J Exp Med 202:1031–1036Google Scholar
  5. Cary LA, Cooper JA (2000) Molecular switches in lipid rafts. Nature 404:945–947PubMedCrossRefGoogle Scholar
  6. Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, Longworth SA, Vinup KE, Mrass P, Oliaro J, Killeen N, Orange JS, Russell SM, Weninger W, Reiner SL (2007) Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315:1687–1691PubMedCrossRefGoogle Scholar
  7. Daniels MA, Teixeiro E, Gill J, Hausmann B, Roubaty D, Holmberg K, Werlen G, Hollander GA, Gascoigne NR, Palmer E (2006) Thymic selection threshold defined by compartmentalization of Ras/MAPK signalling. Nature 444:724–729PubMedCrossRefGoogle Scholar
  8. Fernandez-Miguel G, Alarcon B, Iglesias A, Bluethmann H, Alvarez-Mon M, Sanz E, de la Hera A (1999) Multivalent structure of an alphabetaT cell receptor. Proc Natl Acad Sci U S A 96:1547–1552PubMedCrossRefGoogle Scholar
  9. Filby A, Seddon B, Veldhoen M, Sanchez-Morgado J, Smida M, Lindquist JA, Schraven B, Zamoyska R (2007) Fyn regulates the duration of TCR engagement needed for commitment to effector function. J Immunol 179:4635–4644PubMedGoogle Scholar
  10. Gil D, Schamel WW, Montoya M, Sanchez-Madrid F, Alarcon B (2002) Recruitment of Nck by CD3 epsilon reveals a ligand-induced conformational change essential for T cell receptor signaling and synapse formation. Cell 109:901–912PubMedCrossRefGoogle Scholar
  11. Gil D, Schrum AG, Alarcon B, Palmer E (2005) T cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J Exp Med 201:517–522PubMedCrossRefGoogle Scholar
  12. Gravestein LA, Amsen D, Boes M, Calvo CR, Kruisbeek AM, Borst J (1998) The TNF receptor family member CD27 signals to Jun N-terminal kinase via Traf-2. Eur J Immunol 28:2208–2216PubMedCrossRefGoogle Scholar
  13. Kawabuchi M, Satomi Y, Takao T, Shimonishi Y, Nada S, Nagai K, Tarakhovsky A, Okada M (2000) Transmembrane phosphoprotein Cbp regulates the activities of Src-family tyrosine kinases. Nature 404:999–1003PubMedCrossRefGoogle Scholar
  14. Kesti T, Ruppelt A, Wang JH, Liss M, Wagner R, Taskén K, Saksela K (2007) Reciprocal regulation of SH3 and SH2 domain binding via tyrosine phosphorylation of a common site in CD3epsilon. J Immunol 179:878–885PubMedGoogle Scholar
  15. Klamt S, Saez-Rodriguez J, Lindquist JA, Simeoni L, Gilles ED (2006) A methodology for the structural and functional analysis of signaling and regulatory networks. BMC Bioinformatics 7:56PubMedCrossRefGoogle Scholar
  16. Minguet S, Swamy M, Alarcon B, Luescher IF, Schamel WW (2007) Full activation of the T cell receptor requires both clustering and conformational changes at CD3. Immunity 26:43–54PubMedCrossRefGoogle Scholar
  17. Okada M, Nada S, Yamanashi Y, Yamamoto T, Nakagawa H (1991) CSK: a protein-tyrosine kinase involved in regulation of src family kinases. J Biol Chem 266:24249–24252PubMedGoogle Scholar
  18. Osman N, Turner H, Lucas S, Reif K, Cantrell DA (1996) The protein interactions of the immunoglobulin receptor family tyrosine-based activation motifs present in the T cell receptor zeta subunits and the CD3 gamma, delta and epsilon chains. Eur J Immunol 26:1063–1068PubMedCrossRefGoogle Scholar
  19. Saez-Rodriguez J, Simeoni L, Lindquist JA, Hemenway R, Bommhardt U, Arndt B, Haus UU, Weismantel R, Gilles ED, Klamt S, Schraven B (2007) A logical model provides insights into T cell receptor signaling. PLoS Comput Biol 3:e163PubMedCrossRefGoogle Scholar
  20. San Jose E, Sahuquillo AG, Bragado R, Alarcon B (1998) Assembly of the TCR/CD3 complex: CD3 epsilon/delta and CD3 epsilon/gamma dimers associate indistinctly with both TCR alpha and TCR beta chains. Evidence for a double TCR heterodimer model. Eur J Immunol 28:12–21CrossRefGoogle Scholar
  21. Sicheri F, Moarefi I, Kuriyan J (1997) Crystal structure of the Src family tyrosine kinase Hck. Nature 385:602–609PubMedCrossRefGoogle Scholar
  22. Stefanová I, Hemmer B, Vergelli M, Martin R, Biddison WE, Germain RN (2003) TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nat Immunol 4:248–254PubMedCrossRefGoogle Scholar
  23. Takeuchi S, Takayama Y, Ogawa A, Tamura K, Okada M (2000) Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk. J Biol Chem 275:29183–29186PubMedCrossRefGoogle Scholar
  24. Torgersen KM, Vang T, Abrahamsen H, Yaqub S, Horejsi V, Schraven B, Rolstad B, Mustelin T, Tasken K (2001) Release from tonic inhibition of T cell activation through transient displacement of C-terminal Src kinase (Csk) from lipid rafts. J Biol Chem 276:29313–29318PubMedCrossRefGoogle Scholar
  25. Varma R, Campi G, Yokosuka T, Saito T, Dustin ML (2006) T cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity 25:117–127PubMedCrossRefGoogle Scholar
  26. Xu W, Harrison SC, Eck MJ (1997) Three-dimensional structure of the tyrosine kinase c-Src. Nature 385:595–602PubMedCrossRefGoogle Scholar
  27. Yasuda K, Nagafuku M, Shima T, Okada M, Yagi T, Yamada T, Minaki Y, Kato A, Tani-Ichi S, Hamaoka T, Kosugi A (2002) Cutting edge: Fyn is essential for tyrosine phosphorylation of Csk-binding protein/phosphoprotein associated with glycolipid-enriched microdomains in lipid rafts in resting T cells. J Immunol 169:2813–2817PubMedGoogle Scholar
  28. Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A, Tokunaga M, Dustin ML, Saito T (2005) Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76. Nat Immunol 6:1253–1262PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Institute of Molecular and Clinical ImmunologyOtto-von-Guericke UniversityMagdeburgGermany

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