MHC class I bound to an immunodominant Theileria parva epitope demonstrates unconventional presentation to T cell receptors.
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.
The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom.
Isabel K
IK
Macdonald
Maria
M
Harkiolaki
Lawrence
L
Hunt
Timothy
T
Connelley
A Victoria
AV
Carroll
Niall D
ND
MacHugh
Simon P
SP
Graham
E Yvonne
EY
Jones
W Ivan
WI
Morrison
Darren R
DR
Flower
Shirley A
SA
Ellis
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002417:Cattle; D003461:Crystallography; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding / Q000276:immunology / Q000502:physiology; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D016797:Theileria parva / Q000276:immunology*
D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell