Structure-based design of a bispecific receptor mimic that inhibits T cell responses to a superantigen
| Autor: | Goutam Gupta, N. M. Lehnert, Bruce E. Lehnert, David L. Allen, Beth Allen, Patrick R. Shiflett, Michael Chen, P. Catasti |
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| Rok vydání: | 2001 |
| Předmět: |
Receptor complex
T cell Receptors Antigen T-Cell alpha-beta Recombinant Fusion Proteins T-Lymphocytes Genetic Vectors Molecular Sequence Data chemical and pharmacologic phenomena Lymphocyte Activation Protein Engineering Biochemistry Enterotoxins Structure-Activity Relationship Antigen MHC class I Superantigen medicine Humans Amino Acid Sequence Receptor biology Chemistry Antigen processing T-cell receptor Molecular Mimicry HLA-DR Antigens Growth Inhibitors Peptide Fragments Cell biology medicine.anatomical_structure Immunology biology.protein Interleukin-2 Immunosuppressive Agents |
| Zdroj: | Biochemistry. 40(14) |
| ISSN: | 0006-2960 |
| Popis: | Key surface proteins of pathogens and their toxins bind to the host cell receptors in a manner that is quite different from the way the natural ligands bind to the same receptors and direct normal cellular responses. Here we describe a novel strategy for "non-antibody-based" pathogen countermeasure by targeting the very same "alternative mode of host receptor binding" that the pathogen proteins exploit to cause infection and disease. We have chosen the Staphylococcus enterotoxin B (SEB) superantigen as a model pathogen protein to illustrate the principle and application of our strategy. SEB bypasses the normal route of antigen processing by binding as an intact protein to the complex formed by the MHC class II receptor on the antigen-presenting cell and the T cell receptor. This alternative mode of binding causes massive IL-2 release and T cell proliferation. A normally processed antigen requires all the domains of the receptor complex for its binding, whereas SEB requires only the alpha1 subunit (DRalpha) of the MHC class II receptor and the variable beta subunit (TCRVbeta) of the T cell receptor. This prompted us to design a bispecific chimera, DRalpha-linker-TCRVbeta, that acts as a receptor mimic and prevents the interaction of SEB with its host cell receptors. We have adopted (GSTAPPA)(2) as the linker sequence because it supports synergistic binding of DRalpha and TCRVbeta to SEB and thereby makes DRalpha-(GSTAPPA)(2)-TCRVbeta as effective an SEB binder as the native MHC class II-T cell receptor complex. Finally, we show that DRalpha-(GSTAPPA)(2)-TCRVbeta inhibits SEB-induced IL-2 release and T cell proliferation at nanomolar concentrations. |
| Databáze: | OpenAIRE |
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