Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition.
Improving T cell Ags by altering MHC anchor residues is a common strategy used to enhance peptide vaccines, but there has been little assessment of how such modifications affect TCR binding and T cell recognition. In this study, we use surface plasmon resonance and peptide-MHC tetramer binding at the cell surface to demonstrate that changes in primary peptide anchor residues can substantially and unpredictably alter TCR binding. We also demonstrate that the ability of TCRs to differentiate between natural and anchor-modified heteroclitic peptides distinguishes T cells that exhibit a strong preference for either type of Ag. Furthermore, we show that anchor-modified heteroclitic peptides prime T cells with different TCRs compared with those primed with natural Ag. Thus, vaccination with heteroclitic peptides may elicit T cells that exhibit suboptimal recognition of the intended natural Ag and, consequently, impaired functional attributes in vivo. Heteroclitic peptide-based immune interventions therefore require careful evaluation to ensure efficacy in the clinic.
Cole
David K
DK
Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom.
Edwards
Emily S J
ES
Wynn
Katherine K
KK
Clement
Mathew
M
Miles
John J
JJ
Ladell
Kristin
K
Ekeruche
Julia
J
Gostick
Emma
E
Adams
Katherine J
KJ
Skowera
Ania
A
Peakman
Mark
M
Wooldridge
Linda
L
Price
David A
DA
Sewell
Andrew K
AK
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D009154:Mutation; D009842:Oligopeptides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019151:Peptide Library; D011485:Protein Binding / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D020349:Surface Plasmon Resonance; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C408902:MHC binding peptide; D009842:Oligopeptides; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell