Contribution of the PD-1 ligands/PD-1 signaling pathway to dendritic cell-mediated CD4+ T cell activation |
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Authors: | Kuipers Harmjan Muskens Femke Willart Monique Hijdra Daniëlle van Assema Friso B J Coyle Anthony J Hoogsteden Henk C Lambrecht Bart N |
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Affiliation: | Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands. |
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Abstract: | Dendritic cells (DC) are extremely proficient inducers of naïve CD4+ T cell activation due to their high expression level of peptide‐MHC and an array of accessory molecules involved in cell migration, adhesion and co‐signaling, including PD‐1 ligand 1 (PD‐L1) and PD‐1 ligand 2 (PD‐L2). Whether PD‐L1 and PD‐L2 have a stimulatory or inhibitory function is a matter of debate, and could be partially dependent on the model system used. In this study we examined the role of PD‐L1 and PD‐L2 expressed by DC in naïve CD4+ T cell activation in a more physiologically relevant model system, using OVA‐specific T cells in combination with various levels of TCR stimulation. Overexpression of PD‐L1 or PD‐L2 by DC did not inhibit T cell proliferation, even when B7–1 and B7–2 mediated costimulation was absent, although IL‐2 production was consistently decreased. Surprisingly, blocking PD‐L1 and PD‐L2 with soluble programmed death‐1 (sPD‐1) also inhibited T cell activation, probably via reverse signaling via PD‐L1 and/or PD‐L2 into DC, leading to reduced DC maturation. This study suggests a relatively minor contribution of PD‐1 ligands in DC‐driven CD4+ T cell activation and provides evidence for reverse signaling by PD‐L1 and PD‐L2 into DC, resulting in a suppressive DC phenotype. |
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Keywords: | Costimulation Dendritic cells PD‐1 PD‐L1 PD‐L2 |
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