Variation in epitopes of infectious pathogens inhibits various effector functions of T lymphocytes through antagonism of the T-cell receptor. However, a more powerful strategy for immune evasion would be to prevent the induction of T-cell responses. We report here mutual 'interference' with the priming of human T-cell responses by a pair of naturally occurring variants of a malaria cytotoxic T-cell epitope. Interference with priming also occurs in vivo for a murine malaria T-cell epitope. Reshaping of the T-cell repertoire by such immune interference during naive T-cell induction may provide a general mechanism for observed patterns of immunodominance and persistence by many polymorphic pathogens.

The immunodominant CD4 T cell epitope region, Th2R, of the circumsporozoite protein of Plasmodium falciparum is highly polymorphic. Such variation might be utilized by the parasite to escape from or interfere with CD4 T cell effector functions. Here, we show that costimulation with naturally occurring altered peptide ligands (APL) can induce a rapid change from IFNgamma production to the immunosuppressive mediator interleukin 10 (IL-10). This mechanism may contribute to the low levels of T cell responses observed to this pathogen in malaria-endemic areas.

Natural immunity to malaria is characterized by low level CD4 T cell reactivity detected by either lymphoproliferation or IFN-γ secretion. Here we show a doubling in the detection rate of responders to the carboxyl terminus of circumsporozoite protein (CS) of Plasmodium falciparum by employing three T cell assays simultaneously: rapid IFN-γ secretion (ex vivo ELISPOT), IFN-γ secretion after reactivation of memory T cells and expansion in vitro (cultured ELISPOT), and lymphoproliferation. Remarkably, for no individual peptide did a positive response for one T cell effector function correlate with any other. Thus these CS epitopes elicited unique T cell response patterns in malaria-exposed donors. Novel or important epitope responses may therefore be missed if only one T cell assay is employed. A borderline correlation was found between anti-CS Ab levels and proliferative responses, but no correlation was found with ex vivo or cultured IFN-γ responses. This suggested that the proliferating population, but not the IFN-γ-secreting cells, contained cells that provide help for Ab production. The data suggest that natural immunity to malaria is a complex function of T cell subgroups with different effector functions and has important implications for future studies of natural T cell immunity.