Major Histocompatibility Complex and T Cell Interactions of a Universal T Cell Epitope from Plasmodium falciparum Circumsporozoite Protein
| Autor: | Luz Mary Salazar, Lawrence J. Stern, Thomas O. Cameron, Elizabeth Nardin, Manuel E. Patarroyo, Luis Eduardo Vargas, Carlos Parra-Lopez, J. Mauricio Calvo-Calle |
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| Rok vydání: | 2006 |
| Předmět: |
CD4-Positive T-Lymphocytes
Models Molecular T-Lymphocytes T cell Molecular Sequence Data Plasmodium falciparum Protozoan Proteins Epitopes T-Lymphocyte Biology Major histocompatibility complex Biochemistry Epitope Major Histocompatibility Complex Antigen medicine Animals Humans Biotinylation Amino Acid Sequence Molecular Biology Linear epitope HLA-DR Antigens Cell Biology MHC restriction Virology Molecular biology Circumsporozoite protein medicine.anatomical_structure biology.protein CD8 HLA-DRB1 Chains Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 281:14907-14917 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m511571200 |
| Popis: | A 20-residue sequence from the C-terminal region of the circumsporozoite protein of the malaria parasite Plasmodium falciparum is considered a universal helper T cell epitope because it is immunogenic in individuals of many major histocompatibility complex (MHC) haplotypes. Subunit vaccines containing T* and the major B cell epitope of the circumsporozoite protein induce high antibody titers to the malaria parasite and significant T cell responses in humans. In this study we have evaluated the specificity of the T* sequence with regard to its binding to the human class II MHC protein DR4 (HLA-DRB1*0401), its interactions with antigen receptors on T cells, and the effect of natural variants of this sequence on its immunogenicity. Computational approaches identified multiple potential DR4-binding epitopes within T*, and experimental binding studies confirmed the following two tight binding epitopes: one located toward the N terminus (the T*-1 epitope) and one at the C terminus (the T*-5 epitope). Immunization of a human DR4 volunteer with a peptide-based vaccine containing the T* sequence elicited CD4+ T cells that recognize each of these epitopes. Here we present an analysis of the immunodominant N-terminal epitope T*-1. T*-1 residues important for interaction with DR4 and with antigen receptors on T*-specific T cells were mapped. MHC tetramers carrying DR4/T*-1 MHC-peptide complexes stained and efficiently stimulated these cells in vitro. T*-1 overlaps a region of the protein that has been described as highly polymorphic; however, the particular T*-1 residues required for anchoring to DR4 were highly conserved in Plasmodium sequences described to date. |
| Databáze: | OpenAIRE |
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