title: Extensive polymorphism and evidence of immune selection in a highly dominant antigen recognized by bovine CD8 T cells specific for Theileria annulata.
abstract: Although parasite strain-restricted CD8 T cell responses have been described for several protozoa, the precise role of antigenic variability in immunity is poorly understood. The tick-borne protozoan parasite Theileria annulata infects leukocytes and causes an acute, often fatal lymphoproliferative disease in cattle. Building on previous evidence of strain-restricted CD8 T cell responses to T. annulata, this study set out to identify and characterize the variability of the target antigens. Three antigens were identified by screening expressed parasite cDNAs with specific CD8 T cell lines. In cattle expressing the A10 class I major histocompatibility complex haplotype, A10-restricted CD8 T cell responses were shown to be focused entirely on a single dominant epitope in one of these antigens (Ta9). Sequencing of the Ta9 gene from field isolates of T. annulata demonstrated extensive sequence divergence, resulting in amino acid polymorphism within the A10-restricted epitope and a second A14-restricted epitope. Statistical analysis of the allelic sequences revealed evidence of positive selection for amino acid substitutions within the region encoding the CD8 T cell epitopes. Sequence differences in the A10-restricted epitope were shown to result in differential recognition by individual CD8 T cell clones, while clones also differed in their ability to recognize different alleles. Moreover, the representation of these clonal specificities within the responding CD8 T cell populations differed between animals. As well as providing an explanation for incomplete protection observed after heterologous parasite challenge of vaccinated cattle, these results have important implications for the choice of antigens for the development of novel subunit vaccines.
authors.affiliation: The Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Roslin, Midlothian EH25 9RG, United Kingdom.
authors.forename: Niall D
authors.initials: ND
authors.lastname: MacHugh
authors.forename: William
authors.initials: W
authors.lastname: Weir
authors.forename: Alison
authors.initials: A
authors.lastname: Burrells
authors.forename: Regina
authors.initials: R
authors.lastname: Lizundia
authors.forename: Simon P
authors.initials: SP
authors.lastname: Graham
authors.forename: Evans L
authors.initials: EL
authors.lastname: Taracha
authors.forename: Brian R
authors.initials: BR
authors.lastname: Shiels
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
authors.forename: W Ivan
authors.initials: WI
authors.lastname: Morrison
mesh_terms: D000818:Animals; D000953:Antigens, Protozoan / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002417:Cattle; D002469:Cell Separation; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology; D005434:Flow Cytometry; D008297:Male; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D016796:Theileria annulata / Q000235:genetics* / Q000276:immunology*; D013801:Theileriasis / Q000235:genetics / Q000276:immunology
chemical_list: D000953:Antigens, Protozoan; D018984:Epitopes, T-Lymphocyte