The bovine CD8+ T-cell response to Theileria parva displays epitope immunodominance and oligoclonality

Species: RuminantsTheileria parva is an intracellular protozoal parasite which causes East Coast Fever (ECF), a major constraint to cattle production in eastern and southern Africa. Characteristics of the protective CD8+ T-cell response against T. parva suggest it is focused on a limited number of immunodominant epitopes that exhibit polymorphism between parasite strains. The recent identification of antigens recognised by T. parva-specific CD8+ T-cells has created new opportunities in the development of a subunit vaccine, and permitted the specificity of the CD8+ response to be examined. Cyotoxicity assays with peptide-loaded targets, and analyses of TCRBV gene usage have been used to study the antigen specificity and clonal composition of the CD8+ memory population in T. parva immune animals. Analyses of large panels of T. parva-specific CD8+ T-cell clones from memory T-cells of immune animals homozygous for MHC haplotypes expressing either the A10 or A18 class I specificities, revealed that over 65% of the response was directed against a single immunodominant epitope (Tp1.1 for A18 and Tp2.2. for A10). TCRB-chain sequence analysis showed that for each immunodominant epitope the antigen-specific T-cells were polyclonal but dominated by large oligo-clonal expansions. These clonal expansions utilized different VB gene segments in different animals. Importantly, using a newly developed bovine TCRB-CDR3 heteroduplex assay, it has been possible to identify the same large T-cell clonal expansions in vivo following challenge with T. parva, indicating that the immunodominant populations of CD8+ T-cells observed in in vitro cultures are representative of the memory population present in vivo. This work provides the first definitive demonstration of immunodominance in a CD8+ T-cell response to a protozoan parasite, providing an explanation for the incomplete cross-protection between T. parva strains and has important implications for the design of a subunit vaccine.