PD-1 signaling in primary T cells


  • James L. Riley

    1. Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, The University of Pennsylvania, Philadelphia, PA, USA.
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James L. Riley
Department of Pathology and Laboratory Medicine
Abramson Family Cancer Research Institute
University of Pennsylvania
421 Curie Blvd, BRB II/III, Room:556
Philadelphia, PA 19104 USA
Tel.: +1 215 573 6792
Fax: +1 215 573 8590
e-mail: rileyj@exchange.upenn.edu


Summary:  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.