Abstract
Many pathogens, including the malaria parasite Plasmodium falciparum, display high levels of polymorphism within T-cell epitope regions of proteins associated with protective immunity. The T-cell epitope variants are often non-cross-reactive. Herein, we show in a murine model, which modifies a protective CD8 T-cell epitope from the circumsporozoite protein (CS) of Plasmodium berghei (SYIPSAEKI), that simultaneous or sequential co-stimulation with two of its putative similarly non-cross-reactive altered peptide ligand (APL) epitopes (SYIPSAEDI or SYIPSAEAI) has radically different effects on immunity. Hence, co-immunization or sequential stimulation in vivo of SYIPSAEKI with its APL antagonist SYIPSAEDI decreases immunity to both epitopes. By contrast, co-immunization with SYIPSAEAI has no apparent initial effect, but it renders the immune response to SYIPSAEKI resistant to being turned off by subsequent immunization with SYIPSAEDI. These results suggest a novel strategy for vaccines that target polymorphic epitopes potentially capable of mutual immune interference in the field, by initiating an immune response by co-immunization with the desired index epitope, together with a carefully selected “potentiator” APL peptide.
Highlights
Foreign epitopes complexed with host MHC molecules are the target of recognition by cognate antigen-specific T cells
CD8 T-cell epitope variants causing Altered peptide ligand (APL) antagonism and immune interference have been identified in Plasmodium falciparum and are major contributors to the parasite population structure observed in malaria-endemic regions of the world [2, 3]
The immune interference observed with KI + DI immunization appeared unlikely to be due to the DC-loading protocol but suggests inhibitory effects were mediated by variant DI
Summary
Foreign epitopes complexed with host MHC molecules are the target of recognition by cognate antigen-specific T cells. No KI-specific IFNγ secreting cells were detected in mice immunized with DI-pulsed DCs, confirming that priming with DI did not induce cross-reactive T cells. These data suggest that epitope variant AI does not interfere with KI-specific T cell priming when presented together with KI in vivo, indicating a functional difference between the two altered peptide variants AI and DI.
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