PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion

Eur J Immunol. 2005 Dec;35(12):3561-9. doi: 10.1002/eji.200526347.


The B7 family member programmed death ligand 2 (PD-L2) has been implicated in both positive and negative regulation of T cell activity. In this study, we demonstrate that on human T cells, PD-L2 acts only as a negative regulator of T cell activity, inhibiting proliferation, IL-2 production, and IFN-gamma production via its interaction with programmed death-1 (PD-1). This study also shows a novel role for PD-1 in inhibiting beta1 and beta2 integrin-mediated adhesion. PD-L2 inhibition of T cell function involves modulation of the phosphoinositide 3-OH kinase (PI 3-K)/AKT and extracellular signal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathways, with PD-L2 inhibiting anti-CD3-induced AKT phosphorylation within minutes and ERK phosphorylation after hours. Analysis of phosphatase activity of Src homology 2 domain-containing tyrosine phosphatase (SHP)-1 and SHP-2 in response to anti-CD3 mAb or anti-CD3 mAb + PD-L2 stimulation revealed that while SHP-1 phosphatase activity is not affected by stimulation, SHP-2 phosphatase activity is significantly increased by anti-CD3 mAb + PD-L2 stimulation. Anti-CD3 mAb + PD-L2 stimulation also increased the level of SHP-2 associated with the PD-1 receptor. These results suggest that catalytically active SHP-2 associated with the PD-1 receptor is involved in modulating T cell function.

MeSH terms

  • Antigens, CD / immunology
  • Antigens, CD / metabolism
  • Antigens, CD / physiology*
  • Apoptosis Regulatory Proteins / immunology
  • Apoptosis Regulatory Proteins / metabolism
  • Apoptosis Regulatory Proteins / physiology*
  • CD18 Antigens / metabolism
  • Cell Adhesion / immunology
  • Cell Adhesion Molecules / physiology
  • Cell Proliferation*
  • Cells, Cultured
  • Cytokines / biosynthesis*
  • Down-Regulation / immunology
  • Growth Inhibitors / physiology
  • Humans
  • Integrin beta1 / metabolism
  • Integrins / physiology*
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Intercellular Signaling Peptides and Proteins / physiology*
  • Interferon-gamma / antagonists & inhibitors
  • Interferon-gamma / biosynthesis
  • Interleukin-2 / antagonists & inhibitors
  • Interleukin-2 / biosynthesis
  • Ligands
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*


  • Antigens, CD
  • Apoptosis Regulatory Proteins
  • CD18 Antigens
  • Cell Adhesion Molecules
  • Cytokines
  • Growth Inhibitors
  • Integrin beta1
  • Integrins
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-2
  • Ligands
  • PDCD1 protein, human
  • PDCD1LG2 protein, human
  • Programmed Cell Death 1 Ligand 2 Protein
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma