Knezevic, Lea, Wachsmann, Tassilo L. A., Francis, Ore, Dockree, Tamsin , Bridgeman, John S., Wouters, Anne, de Wet, Ben, Cole, David K., Clement, Matthew, McLaren, James E., Gostick, Emma, Ladell, Kristin, Llewellyn-Lacey, Sian, Price, David A., Van Den Berg, Hugo, Tabi, Zsuzsanna, Sessions, Richard B., Heemskerk, Mirjam H. M. and Wooldridge, Linda (2023) High-affinity CD8 variants enhance the sensitivity of pMHCI antigen recognition via low-affinity TCRs. Journal of Biological Chemistry, 299 (8). 104981. doi:10.1016/j.jbc.2023.104981 ISSN 0021-9258.

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Abstract

The recognition of cell surface presented peptide-Major Histocompatibility Complex Class I (pMHCI) molecules by CD8 T-cells involves cooperative binding of the T-cell receptor (TCR) and CD8 co-receptor. CD8 T-cell antigen specificity is conferred by the TCR, whilst CD8 acts to stabilize the TCR/pMHCI complex and enhance T-cell antigen sensitivity. Earlier work has shown that the sensitivity of antigen recognition can be regulated in vitro by altering the strength of the pMHCI/CD8 interaction. Here, we characterize two CD8 variants with an enhanced affinity for MHCI that remains below the affinity threshold at which non-specific activation is observed. In model systems, expression of these CD8 variants preferentially enhanced pMHCI antigen recognition in the context of low-affinity TCRs. When combined with MHCI-restricted TCRs in primary CD4 T-cells, high affinity CD8 variants could improve T-cell functionality, without loss of antigen specificity. In primary CD8 T-cells, the introduction of high affinity CD8 enhanced T-cell activation compared to endogenous CD8 expression only, although we observed that the introduction of transgenic wild-type CD8 into primary CD8 T-cells also resulted in a similar T-cell effector function enhancement. Collectively, these findings could provide a generically applicable and immediately translatable strategy to augment the therapeutic efficacy of clinically relevant TCRs, which are already being delivered alongside wild-type CD8.

Item Type:	Journal Article
Subjects:	Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology
Divisions:	Faculty of Science, Engineering and Medicine > Science > Mathematics
Library of Congress Subject Headings (LCSH):	Glycoproteins , T cells -- Receptors, HLA histocompatibility antigens, Immunotherapy , Major histocompatibility complex
Journal or Publication Title:	Journal of Biological Chemistry
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Official Date:	August 2023
Dates:	Date Event August 2023 Published 28 June 2023 Available 13 June 2023 Accepted
Volume:	299
Number:	8
Article Number:	104981
DOI:	10.1016/j.jbc.2023.104981
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	19 June 2023
Date of first compliant Open Access:	4 July 2023
RIOXX Funder/Project Grant:	Project/Grant ID RIOXX Funder Name Funder ID 721358 Horizon 2020 Framework Programme http://dx.doi.org/10.13039/100010661 UNSPECIFIED University of Bristol http://dx.doi.org/10.13039/501100000883 097822/Z/11/ZR Wellcome Trust http://dx.doi.org/10.13039/100010269
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