 |
T Cell Epitope Mapping in Endemic Populations: Are We Seeing the Whole Picture?
Summary: Dr. Plebanski is studying malaria-induced immuno-suppression with the goal of developing counter-suppressive vaccines.
Malaria affects approximately 500 million people each year, causing an estimated 2 million deaths. T cells, particularly those able to secrete interferon gamma (IFN-gamma) (T1 cells) have been shown to play a central role in protective immunity against the pre-erythrocytic stages of infection. However, recent Phase I immunogenicity studies in Gambia of the recombinant RTS,S vaccine expressing the circumsporozoite (CS) protein of Plasmodium falciparum emphasized the unusual conclusion from our other studies that T cells induced by infection that are restimulated rapidly to secrete IFN-gamma are different from those that can do so after in vitro expansion with specific peptides. Naturally induced CS-specific T cell reactivity was low in magnitude and broad in specificity, with a range of predicted CS T cell epitopes contributing to responses. Interestingly, another protein of the pre-erythrocytic stage, thrombospondin-related adhesive protein (TRAP), showed a similar broad and low T1 reactivity pattern in large-scale population studies in Kenya. Interestingly, this reactivity was not associated with protection. Studies of T cell reactivity in naturally exposed and vaccinated humans, such as those described above, are important in providing potential epitope targets able to induce protective immunity when incorporated into vaccines. Are we missing protective epitopes in mapping studies? Epitope mapping using overlapping peptides is “assumption free‿ but expensive. Our results indicate that using conventional computer algorithms to predict high-affinity MHC binding peptides is likely to eliminate from mapping studies a range of potentially protective T cell epitopes. Thus, three novel families of peptide MHC-binding modalities are noted: low-affinity (but immunodominant) binding using short anchor residues, high-affinity binding using a new MHC pocket (previously not known to anchor peptides), and the use of carbohydrate molecules in glycopeptides for anchoring to MHC. We suggest that limitations in the spectrum of T cell activities analyzed and in the ability to predict MHC binding has hampered the detection of protective T cell responses.
|
|
|
|
