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High-affinity CD8 variants enhance the sensitivity of pMHCI antigen recognition via low-affinity TCRs

Knezevic, Lea, Wachsmann, Tassilo L.A., Francis, Ore, Dockree, Tamsin, Bridgeman, John S., Wouters, Anne, de Wet, Ben, Cole, David K., Clement, Mathew ORCID:, McLaren, James E., Gostick, Emma, Ladell, Kristin, Llewellyn-Lacey, Sian, Price, David A. ORCID:, van den Berg, Hugo A., 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. 10.1016/j.jbc.2023.104981

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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: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier
ISSN: 0021-9258
Date of First Compliant Deposit: 4 July 2023
Date of Acceptance: 13 June 2023
Last Modified: 07 Sep 2023 01:55

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