title: Amino acid dimorphism and parasite immune evasion: cellular immune responses to a promiscuous epitope of Plasmodium falciparum merozoite surface protein 1 displaying dimorphic amino acid polymorphism are highly constrained.
abstract: Like most other surface-exposed antigens of Plasmodium falciparum, the leading malaria vaccine candidate merozoite surface protein (MSP)-1 contains a large number of dimorphic amino acid positions. This type of diversity is presumed to be associated with parasite immune evasion and represents one major obstacle to malaria subunit vaccine development. To understand the precise role of antigen dimorphism in immune evasion, we have analyzed the flexibility of CD4 T cell immune responses against a semi-conserved sequence stretch of the N-terminal block of MSP-1. While this sequence contains overlapping promiscuous T cell epitopes and is a target for growth inhibitory antibodies, three dimorphic amino acid positions may limit its suitability as component of a multi-epitope malaria vaccine. We have analyzed the CD4 T cell responses in a group of human volunteers immunized with a synthetic malaria peptide vaccine containing a single MSP-143-53 sequence variant. All human T cell lines and HLA-DR- or -DP-restricted T cell clones studied were exclusively specific for the sequence variant used for immunization. Competition peptide binding assays with affinity-purified HLA-DR molecules indicated that dimorphism does not primarily affect HLA binding. Modeling studies of the dominant restricting HLA-DRB1*0801 molecule showed that the dimorphic amino acids represent potential TCR contact residues. Lack of productive triggering of the TCR by MHC/variant peptide ligand complexes thus seems to be the characteristic feature of parasite immune evasion associated with antigen dimorphism.
authors.affiliation: Swiss Tropical Institute, Socinstrasse 57, CH-4002 Basel, Switzerland. Claudia.Daubenberger@unibas.ch
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Daubenberger
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nickel
authors.forename: Carlo
authors.initials: C
authors.lastname: Ciatto
authors.forename: Markus G
authors.initials: MG
authors.lastname: Grütter
authors.forename: Friederike
authors.initials: F
authors.lastname: Pöltl-Frank
authors.forename: Laura
authors.initials: L
authors.lastname: Rossi
authors.forename: Uwe
authors.initials: U
authors.lastname: Siegler
authors.forename: John
authors.initials: J
authors.lastname: Robinson
authors.forename: Oscar
authors.initials: O
authors.lastname: Kashala
authors.forename: Manuel Elkin
authors.initials: ME
authors.lastname: Patarroyo
authors.forename: Gerd
authors.initials: G
authors.lastname: Pluschke
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D019673:Genes, T-Cell Receptor alpha; D019674:Genes, T-Cell Receptor beta; D006684:HLA-DR Antigens / Q000737:chemistry / Q000378:metabolism; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D046911:Macromolecular Substances; D017780:Malaria Vaccines / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D016778:Malaria, Falciparum / Q000276:immunology / Q000517:prevention & control; D020066:Merozoite Surface Protein 1 / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010963:Plasmodium falciparum / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D011110:Polymorphism, Genetic; D011485:Protein Binding
chemical_list: D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; C466440:HLA-DRB1*08:01 antigen; D046911:Macromolecular Substances; D017780:Malaria Vaccines; D020066:Merozoite Surface Protein 1