title: 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 (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.
authors: Department of Oncology, Lausanne University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors: Michael
authors: M
authors: Hebeisen
authors: Lukas
authors: L
authors: Baitsch
authors: Danilo
authors: D
authors: Presotto
authors: Petra
authors: P
authors: Baumgaertner
authors: Pedro
authors: P
authors: Romero
authors: Olivier
authors: O
authors: Michielin
authors: Daniel E
authors: DE
authors: Speiser
authors: Nathalie
authors: N
authors: Rufer
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D000967:Antimony Sodium Gluconate / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000502:physiology; D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D059467:Transcriptome; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D015789:HLA-A2 Antigen; C524942:MIRN155 microRNA, human; C540193:MIrn181 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051746:ZAP-70 Protein-Tyrosine Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D000967:Antimony Sodium Gluconate
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