SHP-1 phosphatase activity counteracts increased T cell receptor affinity
Michael Hebeisen, Lukas Baitsch, Danilo Presotto, Petra Baumgaertner, Pedro Romero, Olivier Michielin, Daniel E. Speiser, Nathalie Rufer
Michael Hebeisen, Lukas Baitsch, Danilo Presotto, Petra Baumgaertner, Pedro Romero, Olivier Michielin, Daniel E. Speiser, Nathalie Rufer
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Research Article Immunology

SHP-1 phosphatase activity counteracts increased T cell receptor affinity

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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Figure 4

Surface expression of costimulatory molecules and coactivatory/inhibitory receptors in CD8+ T cells engineered with TCR of incremental affinities.

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Surface expression of costimulatory molecules and coactivatory/inhibitor...
(A) Surface expression levels of the TNFR-TNFR ligand pairs (i) CD27-CD70 and (ii) HVEM-BTLA as well as of CD28 and CD8β are shown in steady-state conditions (unstimulated cells). TCR variants are presented in order of increased affinity. Data were obtained from 10 independent experiments. (B) Baseline expression levels of Granzyme B and Perforin in CD8+ T cells transduced with TCR variants. Data were obtained from 7 independent experiments. (A and B) Unpaired 2-tailed t test; ***P < 0.001; **P < 0.01; *P < 0.05.