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Knezevic, L.; Wachsmann, T.L.A.; Francis, O.; Dockree, T.; Bridgeman, J.S.; Wouters, A.; ... ; Wooldridge, L. (2023)

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

Article / Letter to editor
CD8+ T cell-mediated recognition of peptide-major histocompatibility complex class I (pMHCI) molecules involves cooperative binding of the T cell receptor (TCR), which confers antigen specificity, and the CD8 coreceptor, which stabilizes the TCR/pMHCI complex. 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 characterized two CD8 variants with moderately enhanced affinities for pMHCI, aiming to boost antigen sensitivity without inducing non-specific activation. Expression of these CD8 variants in model systems preferentially enhanced pMHCI antigen recognition in the context of low-affinity TCRs. A similar effect was observed using primary CD4+ T cells transduced with cancer-targeting TCRs. The introduction of high-affinity CD8 variants also enhanced the functional sensitivity of primary CD8+ T cells expressing cancer-targeting TCRs, but comparable results were obtained using...Show moreCD8+ T cell-mediated recognition of peptide-major histocompatibility complex class I (pMHCI) molecules involves cooperative binding of the T cell receptor (TCR), which confers antigen specificity, and the CD8 coreceptor, which stabilizes the TCR/pMHCI complex. 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 characterized two CD8 variants with moderately enhanced affinities for pMHCI, aiming to boost antigen sensitivity without inducing non-specific activation. Expression of these CD8 variants in model systems preferentially enhanced pMHCI antigen recognition in the context of low-affinity TCRs. A similar effect was observed using primary CD4+ T cells transduced with cancer-targeting TCRs. The introduction of high-affinity CD8 variants also enhanced the functional sensitivity of primary CD8+ T cells expressing cancer-targeting TCRs, but comparable results were obtained using exogenous wild-type CD8. Specificity was retained in every case, with no evidence of reactivity in the absence of cognate antigen. Collectively, these findings highlight a generically applicable mechanism to enhance the sensitivity of low-affinity pMHCI antigen recognition, which could augment the therapeutic efficacy of clinically relevant TCRs.Show less
CD8, human leukocyte antigen (HLA), immunotherapy, major histocompatibility complex (MHC), T cell receptor (TCR)
All authors
Knezevic, L.; Wachsmann, T.L.A.; Francis, O.; Dockree, T.; Bridgeman, J.S.; Wouters, A.; Wet, B. de; Cole, D.K.; Clement, M.; McLaren, J.E.; Gostick, E.; Ladell, K.; Llewellyn-Lacey, S.; Price, D.A.; Berg, H.A. van den; Tabi, Z.; Sessions, R.B.; Heemskerk, M.H.M.; Wooldridge, L.
Date
2023
Journal
Journal of Biological Chemistry
Volume
299
Issue
8
Pages
104981
DOI
doi:10.1016/j.jbc.2023.104981
Link
https://www.sciencedirect.com/science/article/pii/S0021925823020094