CYTOTOXIC T-LYMPHOCYTES TO PLASMODIUM-FALCIPARUM EPITOPES IN AN AREA OF INTENSE AND PERENNIAL TRANSMISSION IN TANZANIA

Studies in The Gambia have provided indirect evidence that cytotoxic T lymphocytes (CTL) play a protective role against malaria in humans an d recently, using allele-specific HLA class I peptide motifs, several peptide epitopes for CTL in four pre-erythrocytic Plasmodium falciparu m antigens have been identified in naturally exposed Gambians. However , CTL levels were low, suggesting that boosting these low levels by im munization might provide substantial protection. In the Kilombero vall ey of Tanzania, malaria transmission is holoendemic and 300 times more intense than in The Gambia. We report here that several of the epitop es identified in The Gambia are also recognized in naturally exposed, partially immune Tanzanian adults and that levels of CTL are similar t o or slightly higher than in Gambian subjects, despite the much higher inoculation rate. We report a new HLA-A2.1-restricted epitope from th e thrombospondin-related anonymous protein (TRAP) and we demonstrate t hat peptide epitopes in TRAP are naturally processed for recognition b y CTL from naturally exposed humans. The common allele of a variable H LA-B7-restricted epitope in the circumsporozoite protein behaved as an altered peptide ligand (APL) with respect to CTL cognate for a rarer allelic variant of this epitope, suggesting that APL antagonism may oc cur in natural CTL responses to P. falciparum. The moderate levels of CTL observed, even in this area of intense malaria transmission, point s to the need to assess candidate vaccines aimed at increasing CTL lev els.