PD-L2:PD-1 involvement in T cell proliferation, cytokine production, and integrin-mediated adhesion.
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.
Saunders
Paul A
PA
Bioassay Department, R&D Systems, Inc., Minneapolis, MN 55413, USA.
Hendrycks
Vana R
VR
Lidinsky
William A
WA
Woods
Melody L
ML
D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008024:Ligands; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D016207:Cytokines; D006131:Growth Inhibitors; D019012:Integrin beta1; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D008024:Ligands; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma