CD8 T-cell responses against the immunodominant Theileria parvapeptide Tp249-59are composed of two distinct populations specific for overlapping 11-mer and 10-mer epitopes

Connelley, Timothy K.;Li, Xiaoying;MacHugh, Niall;Colau, Didier;Morrison, William Ivan;et.al.
(2016) Immunology : the journal of cells, molecules, system and technologies — Vol. 149, n° 2, p. 172-185 (2016)

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Authors
  • Connelley, Timothy K.
    Author
  • Li, Xiaoying
    Author
  • MacHugh, Niall
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  • Colau, Didier
    Author
  • van der Bruggen, PierreUCLouvain
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  • Morrison, William Ivan
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Abstract
Immunity against Theileria parva is associated with CD8 T-cell responses that exhibit immunodominance, focusing the response against limited numbers of epitopes. As candidates for inclusion in vaccines, characterization of responses against immunodominant epitopes is a key component in novel vaccine development. We have previously demonstrated that the Tp249-59 and Tp1214-224 epitopes dominate CD8 T-cell responses in BoLA-A10 and BoLA-18 MHC I homozygous animals, respectively. In this study, peptide-MHC I tetramers for these epitopes, and a subdominant BoLA-A10-restricted epitope (Tp298-106 ), were generated to facilitate accurate and rapid enumeration of epitope-specific CD8 T cells. During validation of these tetramers a substantial proportion of Tp249-59 -reactive T cells failed to bind the tetramer, suggesting that this population was heterogeneous with respect to the recognized epitope. We demonstrate that Tp250-59 represents a distinct epitope and that tetramers produced with Tp50-59 and Tp49-59 show no cross-reactivity. The Tp249-59 and Tp250-59 epitopes use different serine residues as the N-terminal anchor for binding to the presenting MHC I molecule. Molecular dynamic modelling predicts that the two peptide-MHC I complexes adopt structurally different conformations and Tcell receptor β sequence analysis showed that Tp249-59 and Tp250-59 are recognized by non-overlapping T-cell receptor repertoires. Together these data demonstrate that although differing by only a single residue, Tp249-59 and Tp250-59 epitopes form distinct ligands for T-cell receptor recognition. Tetramer analysis of T. parva-specific CD8 T-cell lines confirmed the immunodominance of Tp1214-224 in BoLA-A18 animals and showed in BoLA-A10 animals that the Tp249-59 epitope response was generally more dominant than the Tp250-59 response and confirmed that the Tp298-106 response was subdominant.
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Connelley, T. K., Li, X., MacHugh, N., Colau, D., Graham, S. P., van der Bruggen, P., Taracha, E. L., Gill, A., & Morrison, W. I. (2016). CD8 T-cell responses against the immunodominant Theileria parvapeptide Tp249-59are composed of two distinct populations specific for overlapping 11-mer and 10-mer epitopes. Immunology : the journal of cells, molecules, system and technologies, 149(2), 172-185. https://doi.org/10.1111/imm.12637 (Original work published 2016)