HLA-DR-Promiscuous T Cell Epitopes fromPlasmodium falciparumPre-Erythrocytic-Stage Antigens Restricted by Multiple HLA Class II Alleles

Abstract

Previously, we identified and established the antigenicity of 17 CD8+ T cell epitopes from five P. falciparum Ags that are restricted by multiple common HLA class I alleles. Here, we report the identification of 11 peptides from the same Ags, cicumsporozoite protein, sporozoite surface protein 2, exported protein-1, and liver-stage Ag-1, that bind between at least five and up to 11 different HLA-DR molecules representative of the most common HLA-DR Ags worldwide. These peptides recall lymphoproliferative and cytokine responses in immune individuals experimentally immunized with radiation-attenuated Plasmodium falciparum sporozoites (irradiated sporozoites) or semi-immune individuals naturally exposed to malaria in Irian Jaya or Kenya. We establish that all peptides are recognized by individuals of each of the three populations, and that the frequency and magnitude of helper T lymphocyte responses to each peptide is influenced by the intensity of exposure to P. falciparum sporozoites. Mean frequencies of lymphoproliferative responses are 53.2% (irradiated sporozoites) vs 22.4% (Kenyan) vs 5.8% (Javanese), and mean frequencies of IFN-γ responses are 66.3% (irradiated sporozoites) vs 27.3% (Kenyan) vs 8.7% (Javanese). The identification of HLA class II degenerate T cell epitopes from P. falciparum validates our predictive strategy in a biologically relevant system and supports the potential for developing a broadly efficacious epitope-based vaccine against malaria focused on a limited number of peptide specificities.

Induction of CD4+T cell-dependent CD8+type 1 responses in humans by a malaria DNA vaccine

“…We have previously reported induction of antigen-specific, CD8 ϩ T cell-dependent, genetically restricted, class I-restricted CTL against the same peptides after DNA immunization (5). However, based on murine studies, we concluded that class I-restricted IFN-␥ responses are the primary immune effectors contributing to the long-lasting, preerythrocytic stage-specific protection of mice and humans after immunization with irradiated sporozoites (7,20). Data presented here establish that these responses can be induced in humans by plasmid DNA expressing the PfCSP.…”

ASSOCIATION OF INTERFERON-γ RESPONSES TO PRE-ERYTHROCYTIC STAGE VACCINE CANDIDATE ANTIGENS OF PLASMODIUM FALCIPARUM IN YOUNG KENYAN CHILDREN WITH IMPROVED HEMOGLOBIN LEVELS: XV. ASEMBO BAY COHORT PROJECT

“…5 More recently, it has been reported that some of these pre-erythrocytic stage antigens also contain HLA-DR CD4 + T cell epitopes restricted by multiple HLA class II supertype alleles. 33 Interestingly, a high degree of overlap has been noted between the promiscuous class II CD4 + T cell epitopes reported recently and the degenerate class I CD8 + epitopes identified previously. 5,33 Therefore, we speculate that both CD8 + and CD4 + T cells could respond to some of pre-erythrocytic stage antigens to produce the IFN-␥ observed in this study.…”

Identification ofPlasmodium falciparumantigens by antigenic analysis of genomic and proteomic data

“…Peptides that are capable of binding to the majority of the most common molecules of a given supertype can be identified by in vitro peptide-MHC binding assays, and are designated as supertype binding peptides. A correlation between immunogenicity and the capacity to bind multiple molecules from a given HLA supertype has been documented in several studies (21)(22)(23)(24)(25), and high-affinity binding to the prototype allele of a given supertype has been shown to be highly predictive of supertype binding (17). Herein, we examined whether predictions based on prototype alleles could efficiently identify supertype binders.…”

“…Herein, we examined whether predictions based on prototype alleles could efficiently identify supertype binders. Accordingly, we analyzed Mage2͞3, hepatitis B virus, hepatitis C virus, and Plasmodium protein sequences to examine how many of the previously identified supertype binders (15,(21)(22)(23)(24)(25)(26) were identified by our predictive algorithms (100 nM was selected as the threshold predictive value; Fig. 2).…”