Transmembrane Interactions as Immunotherapeutic Targets: Lessons from Viral Pathogenesis

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 601)

Abstract

Multichain immune recognition receptors (MIRRs) represent a family of structurally related but functionally different surface receptors expressed on different cells of the immune system. A distinctive and common structural characteristic of MIRR family members is that the extracellular recognition domains and intracellular signaling domains are located on separate subunits. How extracellular ligand binding triggers MIRRs and initiates intracellular signal transduction processes is not clear. A novel model of immune signaling, the Signaling Chain HOmoOLigomerization (SCHOOL) model, suggests possible molecular mechanisms and reveals the MIRR transmembrane interactions as universal therapeutic targets for a variety of MIRR-mediated immune disorders. Intriguingly, these interactions have been recently shown to play an important role in human immunodeficiency virus and cytomegalovirus pathogenesis. In this chapter, I demonstrate how the SCHOOL model, together with the lessons learned from viral pathogenesis, can be used practically for rational drug design and the development of new therapeutic approaches to treat a variety of seemingly unrelated disorders, such as T cell-mediated skin diseases and platelet disorders.

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References

  1. Amon, M. A., Ali, M., Bender, V., Chan, Y. N., Toth, I. and Manolios, N. (2006) Lipidation and glycosylation of a T cell antigen receptor (TCR) transmembrane hydrophobic peptide dramatically enhances in vitro and in vivo function. Biochim. Biophys. Acta 1763, 879–888.CrossRefPubMedGoogle Scholar
  2. Arnon, T. I., Achdout, H., Levi, O., Markel, G., Saleh, N., Katz, G., Gazit, R., Gonen-Gross, T., Hanna, J., Nahari, E., Porgador, A., Honigman, A., Plachter, B., Mevorach, D., Wolf, D. G. and Mandelboim, O. (2005) Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat. Immunol. 6, 515–523.CrossRefPubMedGoogle Scholar
  3. Bloch, I., Quintana, F. J., Gerber, D., Cohen, T., Cohen, I. R. and Shai. Y. (2007) T cell inactivation and immunosuppressive activity induced by HIV gp41 via novel interacting motif. FASEB J. 21, 393–401.CrossRefPubMedGoogle Scholar
  4. Call, M. E., Pyrdol, J., Wiedmann, M. and Wucherpfennig, K. W. (2002) The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 111, 967–979.CrossRefPubMedGoogle Scholar
  5. Collier, S., Bolte, A. and Manolios, N. (2006) Discrepancy in CD3-transmembrane peptide activity between in vitro and in vivo T cell inhibition. Scand. J. Immunol. 64, 388–391.CrossRefPubMedGoogle Scholar
  6. Enk, A. H. and Knop, J. (2000) T cell receptor mimic peptides and their potential application in T cell-mediated disease. Int. Arch. Allergy Immunol. 123, 275–281.CrossRefPubMedGoogle Scholar
  7. Loregian, A. and Palu, G. (2005) Disruption of protein-protein interactions: towards new targets for chemotherapy. J. Cell. Physiol. 204, 750–762.CrossRefPubMedGoogle Scholar
  8. Luton, F., Buferne, M., Legendre, V., Chauvet, E., Boyer, C. and Schmitt-Verhulst, A. M. (1997) Role of CD3gamma and CD3delta cytoplasmic domains in cytolytic T lymphocyte functions and TCR/CD3 down-modulation. J. Immunol. 158, 4162–4170.PubMedGoogle Scholar
  9. Manolios, N., Collier, S., Taylor, J., Pollard, J., Harrison, L. C. and Bender, V. (1997) T cell antigen receptor transmembrane peptides modulate T cell function and T cell-mediated disease. Nat. Med. 3, 84–88.CrossRefPubMedGoogle Scholar
  10. Quintana, F. J., Gerber, D., Kent, S. C., Cohen, I. R. and Shai, Y. (2005)HIV-1 fusion peptide targets the TCR and inhibits antigen-specific T cell activation. J. Clin. Invest. 115, 2149–2158.CrossRefPubMedGoogle Scholar
  11. Roifman, C. M. (2004) CD3 delta immunodeficiency. Curr. Opin. Allergy Clin. Immunol. 4, 479–484.CrossRefPubMedGoogle Scholar
  12. Rudd, C. E. (2006) Disabled receptor signaling and new primary immunodeficiency disorders. N. Engl. J. Med. 354, 1874–1877.CrossRefPubMedGoogle Scholar
  13. Sigalov, A. B. (2004) Multichain immune recognition receptor signaling: different players, same game? Trends Immunol. 25, 583–589.CrossRefPubMedGoogle Scholar
  14. Sigalov, A. (2005) Multi-chain immune recognition receptors: spatial organization and signal transduction. Semin. Immunol. 17, 51–64.CrossRefPubMedGoogle Scholar
  15. Sigalov, A. B. (2006) Immune cell signaling: a novel mechanistic model reveals new therapeutic targets. Trends Pharmacol. Sci. 27, 518–524.CrossRefPubMedGoogle Scholar
  16. Sigalov, A., Aivazian, D. and Stern, L. (2004) Homooligomerization of the cytoplasmic domain of the T cell receptor zeta chain and of other proteins containing the immunoreceptor tyrosine-based activation motif. Biochemistry 43, 2049–2061.CrossRefPubMedGoogle Scholar
  17. Vandebona, H., Ali, M., Amon, M., Bender, V. and Manolios, N. (2006) Immunoreceptor transmembrane peptides and their effect on natural killer (NK) cell cytotoxicity. Protein Pept. Lett. 13, 1017–1024.CrossRefPubMedGoogle Scholar
  18. Wang, X. M., Djordjevic, J. T., Kurosaka, N., Schibeci, S., Lee, L., Williamson, P. and Manolios, N. (2002) T cell antigen receptor peptides inhibit signal transduction within the membrane bilayer. Clin. Immunol. 105, 199–207.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Massachusetts Medical SchoolWorcesterUSA

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