Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production
| Autor: | Julia A. Brown, Gordon J. Freeman, Oliver Munoz, Feng-Rong Ma, Clive Wood, David M. Dorfman, Elizabeth L. Sullivan, Edward A. Greenfield |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
CD4-Positive T-Lymphocytes
medicine.medical_specialty Programmed Cell Death 1 Ligand 2 Protein T cell Immunology Programmed Cell Death 1 Receptor Apoptosis Breast Neoplasms Biology Ligands Lymphocyte Activation Binding Competitive B7-H1 Antigen Monocytes Immunoglobulin Fab Fragments Mice Antigens CD Internal medicine medicine Tumor Cells Cultured Immunology and Allergy Animals Humans IL-2 receptor Antigen-presenting cell Cells Cultured Membrane Glycoproteins Follicular dendritic cells Cell Membrane Peripheral tolerance CD28 Proteins Blood Proteins Dendritic Cells Cell biology Endocrinology medicine.anatomical_structure Organ Specificity Antigens Surface B7-1 Antigen Cytokines Intercellular Signaling Peptides and Proteins Female Apoptosis Regulatory Proteins Peptides |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 170(3) |
| ISSN: | 0022-1767 |
| Popis: | 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-γ-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-γ 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. |
| Databáze: | OpenAIRE |
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