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East Coast fever, caused by the tick-borne intracellular apicomplexan parasite Theileria parva, is a highly fatal lymphoproliferative disease of cattle. The pathogenic schizont-induced lymphocyte transformation is a unique cancer-like condition that is reversible with parasite removal. Schizont-infected cell-directed CD8(+) cytotoxic T lymphocytes (CTL) constitute the dominant protective bovine immune response after a single exposure to infection. However, the schizont antigens targeted by T. parva-specific CTL are undefined. Here we show the identification of five candidate vaccine antigens that are the targets of MHC class I-restricted CD8(+) CTL from immune cattle. CD8(+) T cell responses to these antigens were boosted in T. parva-immune cattle resolving a challenge infection and, when used to immunize naïve cattle, induced CTL responses that significantly correlated with survival from a lethal parasite challenge. These data provide a basis for developing a CTL-targeted anti-East Coast fever subunit vaccine. In addition, orthologs of these antigens may be vaccine targets for other apicomplexan parasites.

Evidence that class I major histocompatibility complex-restricted cytotoxic T lymphocytes (CTL) are involved in immunity to malaria has highlighted the potential importance of these cells in protection against intracellular parasites. Parasite-specific CTL are a prominent feature of the immune response of cattle to Theileria parva, a related apicomplexan parasite. The relationship between the appearance of these cells in the blood of immune cattle under challenge and the clearance of infection suggests that they are involved in the control of infection, but direct evidence is lacking that CTL can mediate protection. We have made a quantitative kinetic study of CTL responses in lymph originating from infected lymph nodes in a number of immune cattle under challenge with T. parva. Direct killing activity and the frequency of CTL precursors (CTLp) within responding cell populations were evaluated. A substantial increase in the proportion of CD8+ CTL was observed between days 8 and 11 after challenge. Frequencies of CTLp as high as 1:32 were observed and activity was essentially confined to the large blasting cell fraction. The analogous response in peripheral blood was of lower magnitude and delayed by 1-2 days. The high frequency of CTLp in efferent lymph permitted the adoptive transfer of this activity between immune and naive monozygotic twin calves. In separate experiments, naive calves lethally infected with T. parva were protected by inoculation of up to 10(10) responding CD8+ T cells derived from their immune twins. Elimination of CD8+ T cells within the inoculum abrogated this effect. These findings provide direct evidence that CD8+ T cells can control T. parva infections in immune cattle.