MHC class I bound to an immunodominant Theileria parva epitope demonstrates unconventional presentation to T cell receptors.

Journal article

T cell receptor (TCR) recognition of peptide-MHC class I (pMHC) complexes is a crucial event in the adaptive immune response to pathogens. Peptide epitopes often display a strong dominance hierarchy, resulting in focusing of the response on a limited number of the most dominant epitopes. Such T cell responses may be additionally restricted by particular MHC alleles in preference to others. We have studied this poorly understood phenomenon using Theileria parva, a protozoan parasite that causes an often fatal lymphoproliferative disease in cattle. Despite its antigenic complexity, CD8+ T cell responses induced by infection with the parasite show profound immunodominance, as exemplified by the Tp1(214-224) epitope presented by the common and functionally important MHC class I allele N*01301. We present a high-resolution crystal structure of this pMHC complex, demonstrating that the peptide is presented in a distinctive raised conformation. Functional studies using CD8+ T cell clones show that this impacts significantly on TCR recognition. The unconventional structure is generated by a hydrophobic ridge within the MHC peptide binding groove, found in a set of cattle MHC alleles. Extremely rare in all other species, this feature is seen in a small group of mouse MHC class I molecules. The data generated in this analysis contribute to our understanding of the structural basis for T cell-dependent immune responses, providing insight into what determines a highly immunogenic p-MHC complex, and hence can be of value in prediction of antigenic epitopes and vaccine design.

Authors: Macdonald, I; Harkiolaki, M; Hunt, L; Connelley, T; Carroll, A

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PLoS pathogens
• Volume: 6
• Issue: 10
• Pages: e1001149
• Publication date: 2010-01-01
• DOI: 10.1371/journal.ppat.1001149
• EISSN: 1553-7374
• ISSN: 1553-7366
• Language: English
• Keywords: CD8-Positive T-Lymphocytes; Models, Molecular; Mice; Immunodominant Epitopes; Binding Sites; Cattle; Theileria parva; Amino Acid Sequence; Protein Conformation; Receptors, Antigen, T-Cell; Crystallography; Antigen Presentation; Histocompatibility Antigens Class I; Protein Binding; Animals