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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Neoplasm / immunology
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Antimony Sodium Gluconate / pharmacology
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CD8-Positive T-Lymphocytes / enzymology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / physiology
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Cell Line
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Down-Regulation / immunology
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Extracellular Signal-Regulated MAP Kinases / metabolism
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HLA-A2 Antigen / immunology
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Humans
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Immunotherapy, Adoptive
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Lymphocyte Activation*
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Membrane Proteins / immunology
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Phosphorylation
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Programmed Cell Death 1 Receptor / genetics
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Programmed Cell Death 1 Receptor / metabolism
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Programmed Cell Death 1 Receptor / physiology
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Protein Binding
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Protein Processing, Post-Translational
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
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Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / metabolism*
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Signal Transduction / immunology
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Transcriptome
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ZAP-70 Protein-Tyrosine Kinase / metabolism
Substances
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Antigens, Neoplasm
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CTAG1B protein, human
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HLA-A2 Antigen
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MIRN155 microRNA, human
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MIrn181 microRNA, human
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Membrane Proteins
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MicroRNAs
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell, alpha-beta
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ZAP-70 Protein-Tyrosine Kinase
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Extracellular Signal-Regulated MAP Kinases
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PTPN6 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Antimony Sodium Gluconate