Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells

Man, Stephen; Redman, James E.; Cross, Deborah L; Cole, D.K.; Can, Ilona; Davies, Bethan; Hashimdeen, Shaikh Shimaz; Reid, Reiss; Llewellyn-Lacey, Sian; Miners, Kelly L.; Ladell, Kristin; Lissina, Anna; Brown, Paul E.; Wooldridge, Linda; Price, David A.; Rizkallah, P.J.

doi:10.4049/jimmunol.2000756

Cited by 6 publications

(3 citation statements)

References 52 publications

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“…It would be interesting to further investigate the consequences of the induction of these non-relevant T cells and to study whether they play a role in the observed increased lung pathology in mice vaccinated with MOD2. It has recently been suggested that chemical modification directly alters the immunogenicity of a peptide and could thereby lead to the activation of potentially autoreactive T cells via molecular mimicry of endogenous ligands 24 . Whether this also played a role in the increased lung pathology observed in MOD2-vaccinated mice remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Modified influenza M158–66 peptide vaccination induces non-relevant T-cells and may enhance pathology after challenge

Lanfermeijer,

van de Ven,

van Dijken

et al. 2023

npj Vaccines

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CD8 + T cells are promising targets for vaccination against influenza A virus (IAV) infection. Their induction via peptide vaccination is not trivial, because peptides are weakly immunogenic. One strategy to overcome this is by vaccination with chemically enhanced altered peptide ligands (CPLs), which have improved MHC-binding and immunogenicity. It remains unknown how peptide-modification affects the resulting immune response. We studied the effect of CPLs derived from the influenza M158–66 epitope (GILGFVFTL) on the T-cell response. In HLA-A2*0201 transgenic mice, CPL-vaccination led to higher T-cell frequencies, but only a small percentage of the induced T cells recognized the GILG-wildtype (WT) peptide. CPL-vaccination resulted in a lower richness of the GILG-WT-specific T-cell repertoire and no improved protection against IAV-infection compared to GILG-WT peptide-vaccination. One CPL even appeared to enhance pathology after IAV-challenge. CPL-vaccination thus induces T cells not targeting the original peptide, which may lead to potential unwanted side effects.

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Section: Discussionmentioning

confidence: 99%

Modified influenza M158–66 peptide vaccination induces non-relevant T-cells and may enhance pathology after challenge

Lanfermeijer,

van de Ven,

van Dijken

et al. 2023

npj Vaccines

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show abstract

“…We also surveyed other structures of nonameric peptides bound to HLA-A proteins and found several examples of peptides with large position 6 side chains positioned under the peptide backbone. The structure of the peptide IIGWMWIPV bound to HLA-A2 is a notable example: the conformation of the peptide backbone is nearly identical to that of the neoantigen, yet the tryptophan at position 6 is oriented down towards the base of the groove (43), resembling an intermediate for the under-peptide transition of the neoantigen (Extended Data Fig. 4F).…”

Section: The Flip In the Neoantigen Occurs With A High Energy Peptide...mentioning

confidence: 99%

Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity

Baker,

Ma,

Ayres

et al. 2024

Preprint

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The inherent cross-reactivity of the T cell receptor (TCR) is balanced by high specificity, which often manifests in confounding ways not easily interpretable from static structures. We show here that TCR discrimination between an HLA-A*03:01 (HLA-A3)-restricted public neoantigen derived from mutant PIK3CA and its wild-type (WT) counterpart emerges from motions within the HLA binding groove that vary with the identity of the peptide’s first primary anchor. The motions form a dynamic gate that in the complex with the WT peptide impedes a large conformational change required for TCR binding. The more rigid neoantigen is insusceptible to this limiting dynamic, and with the gate open, is able to transit its central tryptophan residue underneath the peptide backbone to the contralateral side of the HLA-A3 peptide binding groove, facilitating TCR binding. Our findings reveal a novel mechanism driving TCR specificity for a cancer neoantigen that is rooted in the dynamic and allosteric nature of peptide/MHC-I complexes, with implications for resolving long-standing and often confounding questions about the determinants of T cell specificity.

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“…It would be interesting to further investigate the consequences of the induction of these non-relevant T cells and to study whether they play a role in the observed increased lung pathology in mice vaccinated with MOD2. It has recently been suggested that chemical modification directly alters the immunogenicity of a peptide and could thereby lead to the activation of potentially autoreactive T cells via molecular mimicry of endogenous ligands [381]. Whether this also played a role in the increased lung pathology observed in MOD2-vaccinated mice remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Maintenance of the virus-specific CD8+ T-cell repertoire: Implications for vaccine strategies

Lanfermeijer¹

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General introduction and scope of this thesisMethodologies for TCR repertoire analysis PART 1: MAINTENANCE OF THE T-CELL REPERTOIRE Review: How age and infection history shape the antigen-specific CD8 + T-cell repertoire: Implications for vaccination strategies in older adults Aging Cell, 2020 Age and CMV-infection jointly affect the EBV-specific CD8 + T-cell repertoire Frontiers in Aging, 2021 Latent CMV-infection is associated with lower influenza virus-specific memory T-cell frequencies, but not with an impaired T-cell response to acute influenza virus infection Frontiers in Immunology, 2021 Longitudinal characterization of the mumps-specific HLA-A2 restricted T-cell response after mumps virus infection Vaccines, 2021

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Synthetic Peptides with Inadvertent Chemical Modifications Can Activate Potentially Autoreactive T Cells

Abstract: under the Erasmus Scheme. Beamtime was supported by proposals mx10462 and mx14843.

Cited by 6 publications

References 52 publications

Modified influenza M158–66 peptide vaccination induces non-relevant T-cells and may enhance pathology after challenge

Modified influenza M158–66 peptide vaccination induces non-relevant T-cells and may enhance pathology after challenge

Dynamic allostery in the peptide/MHC complex enables TCR neoantigen selectivity

Maintenance of the virus-specific CD8+ T-cell repertoire: Implications for vaccine strategies

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