SHP-1 phosphatase activity counteracts increased T cell receptor affinity

J Clin Invest. 2013 Mar;123(3):1044-56. doi: 10.1172/JCI65325. Epub 2013 Feb 8.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / immunology
  • Antimony Sodium Gluconate / pharmacology
  • CD8-Positive T-Lymphocytes / enzymology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / physiology
  • Cell Line
  • Down-Regulation / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • HLA-A2 Antigen / immunology
  • Humans
  • Immunotherapy, Adoptive
  • Lymphocyte Activation*
  • Membrane Proteins / immunology
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Phosphorylation
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism
  • Programmed Cell Death 1 Receptor / physiology
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / antagonists & inhibitors
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
  • Receptors, Antigen, T-Cell, alpha-beta / genetics
  • Receptors, Antigen, T-Cell, alpha-beta / metabolism*
  • Signal Transduction / immunology
  • Transcriptome
  • ZAP-70 Protein-Tyrosine Kinase / metabolism

Substances

  • Antigens, Neoplasm
  • CTAG1B protein, human
  • HLA-A2 Antigen
  • MIRN155 microRNA, human
  • MIrn181 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell, alpha-beta
  • ZAP-70 Protein-Tyrosine Kinase
  • Extracellular Signal-Regulated MAP Kinases
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6
  • Antimony Sodium Gluconate

Associated data

  • GEO/GSE42922