Pre-erythrocytic T cell immunity in malaria exposed Africans

Flanagan, Katie Louise (2000). Pre-erythrocytic T cell immunity in malaria exposed Africans. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000f96b

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.

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