Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms.

Détails

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Etat: Public
Version: Final published version
ID Serval
serval:BIB_ABB1F0F8CA5E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Fine-Tuning of Optimal TCR Signaling in Tumor-Redirected CD8 T Cells by Distinct TCR Affinity-Mediated Mechanisms.
Périodique
Frontiers in Immunology
Auteur(s)
Presotto D., Erdes E., Duong M.N., Allard M., Regamey P.O., Quadroni M., Doucey M.A., Rufer N., Hebeisen M.
ISSN
1664-3224 (Print)
ISSN-L
1664-3224
Statut éditorial
Publié
Date de publication
2017
Peer-reviewed
Oui
Volume
8
Pages
1564
Langue
anglais
Résumé
Redirecting CD8 T cell immunity with self/tumor-specific affinity-matured T cell receptors (TCRs) is a promising approach for clinical adoptive T cell therapy, with the aim to improve treatment efficacy. Despite numerous functional-based studies, little is known about the characteristics of TCR signaling (i.e., intensity, duration, and amplification) and the regulatory mechanisms underlying optimal therapeutic T cell responses. Using a panel of human SUP-T1 and primary CD8 T cells engineered with incremental affinity TCRs against the cancer-testis antigen NY-ESO-1, we found that upon activation, T cells with optimal-affinity TCRs generated intense and sustained proximal (CD3ζ, LCK) signals associated with distal (ERK1/2) amplification-gain and increased function. In contrast, in T cells with very high affinity TCRs, signal initiation was rapid and strong yet only transient, resulting in poor MAPK activation and low proliferation potential even at high antigen stimulation dose. Under resting conditions, the levels of surface TCR/CD3ε, CD8β, and CD28 expression and of CD3ζ phosphorylation were significantly reduced in those hyporesponsive cells, suggesting the presence of TCR affinity-related activation thresholds. We also show that SHP phosphatases were involved along the TCR affinity gradient, but displayed spatially distinct regulatory roles. While PTPN6/SHP-1 phosphatase activity controlled TCR signaling initiation and subsequent amplification by counteracting CD3ζ and ERK1/2 phosphorylation, PTPN11/SHP-2 augmented MAPK activation without affecting proximal TCR signaling. Together, our findings indicate that optimal TCR signaling can be finely tuned by TCR affinity-dependent SHP-1 and SHP-2 activity, and this may readily be determined at the TCR/CD3 complex level. We propose that these TCR affinity-associated regulations represent potential protective mechanisms preventing high affinity TCR-mediated autoimmune diseases.

Mots-clé
CD3ζ, ERK1/2, NY-ESO-1 antigen, SHP-1, SHP-2 phosphatases, T cell receptor engineering, T cell receptor-peptide-major histocompatibility complex affinity, cancer immunotherapy, hyporesponsiveness
Pubmed
Web of science
Open Access
Oui
Création de la notice
09/12/2017 10:48
Dernière modification de la notice
20/08/2019 16:15
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