Contribution of the PD‐1 ligands/PD‐1 signaling pathway to dendritic cell‐mediated CD4⁺ T cell activation

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 OVAspecific 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.

Induction of Treg by monocyte‐derived DC modulated by vitamin D3 or dexamethasone: Differential role for PD‐L1

“…PD-L1 on VD3-DC is crucial for the acquisition of Treg function by CD4 One explanation may be reverse signaling by PD-L1 into DC. Triggering PD-L1 on DC using sPD-1-Ig resulted in decreased expression of the positive co-stimulatory molecules CD80, CD86 and CD40 and increased IL-10 production [55]. We propose that ligation of PD-L1 on VD3-DC triggers local secretion of high amounts of IL-10 that affect activation and surface marker expression of contacting T cells.…”

Soluble CD200 Correlates With Interleukin-6 Levels in Sera of COPD Patients: Potential Implication of the CD200/CD200R Axis in the Disease Course

“…The rationale behind targeted modulation of the CD200R is that the receptor has been shown to be upregulated on pulmonary myeloid cells even under strong LPS stimulus [13]. Furthermore, unlike other receptor-ligand pairs [39,40], CD200-bearing cells do not mediate downstream signals due to its short cytoplasmic tail that has no signaling motifs. Hence the central response following…”

Identification of PDL-1 as a novel biomarker of sensitizer exposure in dendritic-like cells

“…Two new members of the B7 family have been identified; programmed death ligand-1 (PDL-1) and PDL-2 which comprise ligands for the T cell expressed programmed death receptor-1 (PD-1) (Matsumoto et al, 2004). Several groups have independently revealed dual functions of PDL-1 in regulating T cell responses (Kuipers et al, 2006). Firstly, PDL-1 signals negatively regulate activated T cell function and survival (Freeman et al, 2000).…”