Cytotoxic T-lymphocytes against malaria and tuberculosis: from natural immunity to vaccine design.
1. Mycobacterium tuberculosis and the liver stage of Plasmodium falciparum are intracellular pathogens which are potentially susceptible to cytotoxic T-lymphocytes, a crucial component of the protective immune response to viral infections. Evidence from animal models points to a protective role for cytotoxic T-lymphocytes against M. tuberculosis and P. falciparum, but cytotoxic T-lymphocytes specific for these pathogens have been difficult to identify in man.2. Using a reverse immunogenetic approach, candidate epitopes from selected antigens of P. falciparum and M. tuberculosis were used to detect peptide-specific cytotoxic T-lymphocyte responses in individuals exposed to these pathogens. Cytotoxic T-lymphocyte activity was detected by the 51Cr release cytotoxicity assay and a sensitive ELISPOT assay for single-cell interferon-gamma release.3. In naturally exposed, partially immune Africans in The Gambia, eight largely conserved cytotoxic T-lymphocyte epitopes in P. falciparum, restricted by several different HLA class I alleles, were identified. Several epitopes were also recognized in Tanzanians and cytotoxic T-lymphocytes recognized endogenously processed antigen.4. In tuberculosis patients with HLA-B52, a CD8+ cytotoxic T-lymphocyte epitope was identified in ESAT-6, a secreted antigen specific for M. tuberculosis complex but absent in BCG. Cytotoxic T-lymphocytes exhibited HLA-B52-restricted peptide-specific interferon-gamma release and lytic activity and recognized endogenously processed antigen.5. These studies demonstrate that CD8+ cytotoxic T-lymphocytes specific for mycobacterial and protozoal antigens are induced during natural infections in humans. The identification of these T-cells endorses current strategies to develop cytotoxic T-lymphocyte-inducing vaccines against P. falciparum and M. tuberculosis and highlights candidate antigens for inclusion in subunit vaccines.
Lalvani
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Nuffield Department of Clinical Medicine, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, U.K.
Hill
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D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D000953:Antigens, Protozoan / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D000939:Epitopes / Q000276:immunology; D005714:Gambia; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D008288:Malaria / Q000276:immunology* / Q000517:prevention & control; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013636:Tanzania; D014376:Tuberculosis / Q000276:immunology* / Q000517:prevention & control; D014614:Vaccines, Synthetic
D000942:Antigens, Bacterial; D000953:Antigens, Protozoan; D000939:Epitopes; D014614:Vaccines, Synthetic; D007371:Interferon-gamma