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      Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production.

      The Journal of Immunology Author Choice

      Tumor Cells, Cultured, Animals, Antigens, CD, Antigens, CD274, Antigens, CD80, Antigens, Surface, Apoptosis, immunology, Apoptosis Regulatory Proteins, Binding, Competitive, Blood Proteins, antagonists & inhibitors, biosynthesis, metabolism, Breast Neoplasms, CD4-Positive T-Lymphocytes, Cell Membrane, Cells, Cultured, Cytokines, Dendritic Cells, cytology, Female, Humans, Immunoglobulin Fab Fragments, pharmacology, Intercellular Signaling Peptides and Proteins, Ligands, Lymphocyte Activation, Membrane Glycoproteins, Mice, Monocytes, Organ Specificity, Peptides, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Proteins

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          Abstract

          Programmed death-1 ligand (PD-L)1 and PD-L2 are ligands for programmed death-1 (PD-1), a member of the CD28/CTLA4 family expressed on activated lymphoid cells. PD-1 contains an immunoreceptor tyrosine-based inhibitory motif and mice deficient in PD-1 develop autoimmune disorders suggesting a defect in peripheral tolerance. Human PD-L1 and PD-L2 are expressed on immature dendritic cells (iDC) and mature dendritic cells (mDC), IFN-gamma-treated monocytes, and follicular dendritic cells. Using mAbs, we show that blockade of PD-L2 on dendritic cells results in enhanced T cell proliferation and cytokine production, including that of IFN-gamma and IL-10, while blockade of PD-L1 results in similar, more modest, effects. Blockade of both PD-L1 and PD-L2 showed an additive effect. Both whole mAb and Fab enhanced T cell activation, showing that PD-L1 and PD-L2 function to inhibit T cell activation. Enhancement of T cell activation was most pronounced with weak APC, such as iDCs and IL-10-pretreated mDCs, and less pronounced with strong APC such as mDCs. These data are consistent with the hypothesis that iDC have a balance of stimulatory vs inhibitory molecules that favors inhibition, and indicate that PD-L1 and PD-L2 contribute to the poor stimulatory capacity of iDC. PD-L1 expression differs from PD-L2 in that PD-L1 is expressed on activated T cells, placental trophoblasts, myocardial endothelium, and cortical thymic epithelial cells. In contrast, PD-L2 is expressed on placental endothelium and medullary thymic epithelial cells. PD-L1 is also highly expressed on most carcinomas but minimally expressed on adjacent normal tissue suggesting a role in attenuating antitumor immune responses.

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