Tolerogenic plasmacytoid DC

Abstract

Plasmacytoid DC (pDC) are type-I IFN-producing cells known for their capacity to promote anti-viral innate and adaptive immune responses. Despite their potent anti-viral function, when compared with conventional DC, pDC exhibit poor immunostimulatory ability and their interaction with T cells often favors the generation of Treg. pDC are activated primarily in response to ssRNA and ssDNA through TLR7 and TLR9, respectively, but also through TLR-independent mechanisms. Non-lymphoid tissue pDC, such as those residing in the airways, gut, and liver, play a significant role in regulating mucosal immunity and are critical for the development of tolerance to inhaled or ingested antigens. Herein we discuss properties that define tolerogenic pDC and how their unique characteristics translate into an ability to regulate immunity and promote the development of tolerance. We cover the importance of pDC during intrathymic Treg development and the maintenance of peripheral tolerance, as well as their regulatory role in transplantation, autoimmunity, and cancer. We highlight recent findings regarding danger-associated molecular pattern and PAMP signaling in the regulation of pDC function, and how the ability of pDC to promote tolerance translates into the potential clinical applications of these cells as therapeutic targets to regulate immune reactivity.

Figure 1. Impact of TLR and NOD2 ligation on pDC function

pDC function is markedly affected by recognition of PAMPs. Unlike conventional mDC, pDC produce large amounts of type-I IFN through a IRF-7-dependent mechanism [6]. TLR9 and TLR7 signaling has been shown to reduce the IL-3/IL-10-dependent release of Granzyme B by pDC, which under normal conditions, reduces T cell proliferation. pDC can sense, through TLR7, HCV-RNA physically transferred inside the pDC after cell-to-cell contact with infected cells, inducing type-I IFN secretion [78]. Mouse pDC also express TLR4, which senses LPS resulting in pro-inflammatory cytokine production (IL-6, IL-12, TNFα). In vivo exposure to the NOD2 ligand muramyl dipeptide (MDP) upregulates expression of IFN regulatory factor-4 (IRF-4), a negative regulator of TLR signaling, and impairs the ability of pDC to secrete type-I IFNs and pro-inflammatory cytokines in response to TLR ligands [28]. Moreover, NOD2 ligation upregulates PD-L1 on pDC and reduces their ability to induce allogeneic T cell proliferation.

Figure 2. pDC regulate anti-tumor immunity and can promote tumor escape

(A) pDC are recruited into the tumor microenvironment via multiple receptor-ligand interactions. Interaction of stromal cell-derived factor (SDF)-1/CCL12 with CXCR4 on pDC can upregulate very late Ag (VLA)-5 for transendothelial migration via VCAM-1 and can protect pDC from IL-10-induced apoptosis [71]. CCL20 binding to CCR6 on pDC can recruit pDC to the tumor site [72]. Factors produced within the tumor microenvironment can modulate IFNα production via TLR9 stimulation. pDC cultured with tumor cells can induce IL-10 production by CD4⁺ T cells and CD8⁺ Treg [73, 74]. (B) CD19⁺ pDC in tumor-draining LN (TDLN) produce high levels of IDO which can activate mature Treg via activation of the general control non-depressive kinase 2 (GCN2) pathway of protein synthesis inhibition [38]. Activated Treg can then activate other DC, leading to upregulation of PD-L1 which suppresses anti-tumor T cell responses. pDC-produced IDO and activated Treg can also convert naïve T cells into new Treg. IDO acts in an autocrine manner to suppress pDC production of IL-6, which prevents the conversion of Treg into IL-17-producing Th17 pro-inflammatory cells [76]. IDO also downregulates IFNα production by pDC [77].