Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition

Cole, David ORCID: https://orcid.org/0000-0003-0028-9396, Edwards, Emily ORCID: https://orcid.org/0000-0002-0240-4370, Wynn, Katherine, Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Miles, John James, Ladell, Kristin Ingrid ORCID: https://orcid.org/0000-0002-9856-2938, Ekeruche, Julia, Gostick, Emma, Adams, Katherine J., Skowera, Ania, Peakman, Mark, Wooldridge, Linda, Price, David A. ORCID: https://orcid.org/0000-0001-9416-2737 and Sewell, Andrew K. ORCID: https://orcid.org/0000-0003-3194-3135 2010. Modification of MHC anchor residues generates heteroclitic peptides that alter TCR binding and T cell recognition. The Journal of Immunology 185 (4) , pp. 2600-2610. 10.4049/jimmunol.1000629

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology
Publisher:	American Association of Immunologists
ISSN:	0022-1767
Last Modified:	27 Jul 2023 01:07
URI:	https://orca.cardiff.ac.uk/id/eprint/24905

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