PD-1 signaling in primary T cells.
Programmed death-1 (PD-1) is a cell surface molecule that regulates the adaptive immune response. Engagement of PD-1 by its ligands PD-L1 or PD-L2 transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function. While a great deal is known concerning the biologic roles PD-1 plays in regulating the primary immune response and in T-cell exhaustion, comparatively little is known regarding how PD-1 ligation alters signaling pathways. PD-1 ligation is known to inhibit membrane-proximal T-cell signaling events, while ligation of the related inhibitory molecule cytotoxic T-lymphocyte antigen-4 appears to target more downstream signaling pathways. A major obstacle to an in-depth understanding of PD-1 signaling is the lack of physiologic models in which to study signal transduction. This review focuses on: (i) signaling pathways altered by PD-1 ligation, (ii) factors recruited upon PD-1 phosphorylation, and (iii) exploring the hypothesis that PD-1 ligation induces distinct signals during various stages of immune-cell differentiation. Lastly, we describe models to dissect the function of the PD-1 cytoplasmic tail using primary cells in the absence of agonist antibodies.
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, The University of Pennsylvania, Philadelphia, PA, USA. rileyj@exchange.upenn.edu
James L
JL
Riley
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D060908:CTLA-4 Antigen; D006801:Humans; D051379:Mice; D061026:Programmed Cell Death 1 Receptor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000276:immunology / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6