Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

J Exp Med. 2012 Jun 4;209(6):1201-17. doi: 10.1084/jem.20112741. Epub 2012 May 28.

Abstract

Programmed cell death 1 (PD-1) is a negative costimulatory receptor critical for the suppression of T cell activation in vitro and in vivo. Single cell imaging elucidated a molecular mechanism of PD-1-mediated suppression. PD-1 becomes clustered with T cell receptors (TCRs) upon binding to its ligand PD-L1 and is transiently associated with the phosphatase SHP2 (Src homology 2 domain-containing tyrosine phosphatase 2). These negative costimulatory microclusters induce the dephosphorylation of the proximal TCR signaling molecules. This results in the suppression of T cell activation and blockade of the TCR-induced stop signal. In addition to PD-1 clustering, PD-1-TCR colocalization within microclusters is required for efficient PD-1-mediated suppression. This inhibitory mechanism also functions in PD-1(hi) T cells generated in vivo and can be overridden by a neutralizing anti-PD-L1 antibody. Therefore, PD-1 microcluster formation is important for regulation of T cell activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • Lymphocyte Activation
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Phosphorylation
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Receptors, Antigen, T-Cell / metabolism*
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • Tyrosine / metabolism

Substances

  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Tyrosine
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11