Pre-erythrocytic T cell immunity in malaria exposed Africans

Abstract

Many believe that vaccines are the intervention with the greatest chance of reducing the worldwide burden of malaria. Irradiated sporozoites protect against subsequent malaria challenge, and a vaccine that mimics this stage might be effective. CD4 and CDS T cells are thought to be crucial in protection, but studies of T cell immunity in malaria exposed donors are hampered by widespread nonresponsiveness, to malaria antigens. Most studies of natural T cell immunity measured lymphoproliferation alone, but I found that if 3 T cell assays were employed simultaneously (proliferation, overnight IFN-y ELISPOT, and IFN-y ELISPOT after 14 days culture), that T cell reactivity to circumsporozoite protein (CS) was considerably higher than when using proliferation alone. Responses to individual epitopes failed to correlate over the 3 assays, suggesting that they detect different memory T cell subsets. I investigated the nature of responder cells in the 3 assays, and found ex- vivo ELISPOT responses were mediated by CCR7+ and cultured ELISPOT by CCR7+ cells. I also found a CD4+CD38+ T cell subset that suppressed lymphoproliferation, and might contribute to malaria immunosuppression. The immunodominant T cell epitope regions of CS are highly polymorphic, and I found that altered peptide ligand antagonism operated for variants of a CD4 T cell site. Less polymorphic antigens might be better vaccine candidates, one promising candidate being thrombospondin related adhesive protein (TRAP). I mapped novel CD4 T cell epitopes in TRAP, 16 of which were conserved. I found differences in TRAP T cell reactivity between East and West Africans, and adults and children, which is important since these populations will be recipients of future malaria vaccines. I investigated whether IFN-y ELISPOT responses to TRAP correlated with protection, since IFN-y is thought to be the mechanism by which T cells exert their protective effect, but no protection was found.