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SHP-1 phosphatase activity counteracts increased T cell receptor affinity
Michael Hebeisen, … , Daniel E. Speiser, Nathalie Rufer
Michael Hebeisen, … , Daniel E. Speiser, Nathalie Rufer
Published March 1, 2013; First published February 8, 2013
Citation Information: J Clin Invest. 2013;123(3):1044-1056. https://doi.org/10.1172/JCI65325.
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Categories: Research Article Immunology

SHP-1 phosphatase activity counteracts increased T cell receptor affinity

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Abstract

Anti-self/tumor T cell function can be improved by increasing TCR-peptide MHC (pMHC) affinity within physiological limits, but paradoxically further increases (Kd < 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 (Kd = 5 to 1 μM), those with supraphysiological affinity (Kd = 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.

Authors

Michael Hebeisen, Lukas Baitsch, Danilo Presotto, Petra Baumgaertner, Pedro Romero, Olivier Michielin, Daniel E. Speiser, Nathalie Rufer

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