Major histocompatibility complex and T cell interactions of a universal T cell epitope from Plasmodium falciparum circumsporozoite protein.
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.
Parra-López
Carlos
C
Fundación Instituto de Inmunología de Colombia, Grupo Funcional Inmunología, Carrera 50 No. 26-00, Bogotá, Colombia.
Calvo-Calle
J Mauricio
JM
Cameron
Thomas O
TO
Vargas
Luis E
LE
Salazar
Luz Mary
LM
Patarroyo
Manuel E
ME
Nardin
Elizabeth
E
Stern
Lawrence J
LJ
D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry*; D006684:HLA-DR Antigens / Q000737:chemistry; D059811:HLA-DRB1 Chains; D006801:Humans; D008285:Major Histocompatibility Complex; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism* / Q000469:parasitology*
D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan