Titre
CD8 T cell function and cross-reactivity explored by stepwise increased peptide-HLA versus TCR affinity.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Baumgaertner, P.
Auteure/Auteur
Schmidt, J.
Auteure/Auteur
Costa-Nunes, C.M.
Auteure/Auteur
Bordry, N.
Auteure/Auteur
Guillaume, P.
Auteure/Auteur
Luescher, I.
Auteure/Auteur
Speiser, D.E.
Auteure/Auteur
Rufer, N.
Auteure/Auteur
Hebeisen, M.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1664-3224
Statut éditorial
Publié
Date de publication
2022-08-10
Volume
13
Première page
973986
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Publication Status: epublish
Résumé
Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the "blue peptide assay", an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity.
PID Serval
serval:BIB_16DFBAE86CE1
PMID
Open Access
Oui
Date de création
2022-09-05T07:33:59.974Z
Date de création dans IRIS
2025-05-20T15:46:27Z
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Nom
fimmu-13-973986-1.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by/4.0
Taille
4.46 MB
Format
Adobe PDF
PID Serval
serval:BIB_16DFBAE86CE1.P001
URN
urn:nbn:ch:serval-BIB_16DFBAE86CE12
Somme de contrôle
(MD5):59ec88e77b2bbfed683a3c680c1d169f