SHP-1 phosphatase activity counteracts increased T cell receptor affinity.

Détails

Ressource 1Télécharger: BIB_1DC11F4ABA42.P001.pdf (7240.75 [Ko])
Etat: Public
Version: Author's accepted manuscript
ID Serval
serval:BIB_1DC11F4ABA42
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
SHP-1 phosphatase activity counteracts increased T cell receptor affinity.
Périodique
Journal of Clinical Investigation
Auteur(s)
Hebeisen M., Baitsch L., Presotto D., Baumgaertner P., Romero P., Michielin O., Speiser D.E., Rufer N.
ISSN
1558-8238 (Electronic)
ISSN-L
0021-9738
Statut éditorial
Publié
Date de publication
2013
Volume
123
Numéro
3
Pages
1044-1056
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish. PDF type: Research article
Résumé
Anti-self/tumor T cell function can be improved by increasing TCR-peptide MHC (pMHC) affinity within physiological limits, but paradoxically further increases (K(d) < 1 μM) lead to drastic functional declines. Using human CD8(+) T cells engineered with TCRs of incremental affinity for the tumor antigen HLA-A2/NY-ESO-1, we investigated the molecular mechanisms underlying this high-affinity-associated loss of function. As compared with cells expressing TCR affinities generating optimal function (K(d) = 5 to 1 μM), those with supraphysiological affinity (K(d) = 1 μM to 15 nM) showed impaired gene expression, signaling, and surface expression of activatory/costimulatory receptors. Preferential expression of the inhibitory receptor programmed cell death-1 (PD-1) was limited to T cells with the highest TCR affinity, correlating with full functional recovery upon PD-1 ligand 1 (PD-L1) blockade. In contrast, upregulation of the Src homology 2 domain-containing phosphatase 1 (SHP-1/PTPN6) was broad, with gradually enhanced expression in CD8(+) T cells with increasing TCR affinities. Consequently, pharmacological inhibition of SHP-1 with sodium stibogluconate augmented the function of all engineered T cells, and this correlated with the TCR affinity-dependent levels of SHP-1. These data highlight an unexpected and global role of SHP-1 in regulating CD8(+) T cell activation and responsiveness and support the development of therapies inhibiting protein tyrosine phosphatases to enhance T cell-mediated immunity.
Pubmed
Web of science
Open Access
Oui
Création de la notice
12/04/2013 18:36
Dernière modification de la notice
20/08/2019 13:54
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