The role of plasmacytoid dendritic cells (pDCs) in immunity during viral infections and beyond

Abstract

Type I and III interferons (IFNs) are essential for antiviral immunity and act through two different but complimentary pathways. First, IFNs activate intracellular antimicrobial programs by triggering the upregulation of a broad repertoire of viral restriction factors. Second, IFNs activate innate and adaptive immunity. Dysregulation of IFN production can lead to severe immune system dysfunction. It is thus crucial to identify and characterize the cellular sources of IFNs, their effects, and their regulation to promote their beneficial effects and limit their detrimental effects, which can depend on the nature of the infected or diseased tissues, as we will discuss. Plasmacytoid dendritic cells (pDCs) can produce large amounts of all IFN subtypes during viral infection. pDCs are resistant to infection by many different viruses, thus inhibiting the immune evasion mechanisms of viruses that target IFN production or their downstream responses. Therefore, pDCs are considered essential for the control of viral infections and the establishment of protective immunity. A thorough bibliographical survey showed that, in most viral infections, despite being major IFN producers, pDCs are actually dispensable for host resistance, which is achieved by multiple IFN sources depending on the tissue. Moreover, primary innate and adaptive antiviral immune responses are only transiently affected in the absence of pDCs. More surprisingly, pDCs and their IFNs can be detrimental in some viral infections or autoimmune diseases. This makes the conservation of pDCs during vertebrate evolution an enigma and thus raises outstanding questions about their role not only in viral infections but also in other diseases and under physiological conditions.

Keywords: Homeostasis; Interferon; Plasmacytoid dendritic cells; Tissue; Viral infection.

Fig. 1

Phenotypic and functional description of dendritic cell types. Dendritic cells (DCs) encompass different cell types, including plasmacytoid dendritic cells (pDCs), CD11c^low (CD11c^low Ly6C^high) and CD11c^high (CD11c^high Ly6C^low) transitional dendritic cells (tDCs) and conventional dendritic cells (cDCs), which are divided into type 1 cDCs (cDC1s) and type 2 cDCs (cDC2s). pDCs are characterized by their capacity to produce large amounts of IFN-I/IIIs upon exposure to a large spectrum of TLR7/9 ligands of viral or synthetic origin (e.g., CpG A and B), while CD11c^low Ly6C^high tDCs are activated mainly by CpG-B. IFN-IIIs can also be produced by cDC1s via a TLR3-TRIF-dependentmechanism. At steady state, cDC2s and CD11c^high Ly6C^low tDCs can present antigens (pale blue) associated with MHC class II (MHC-II) for CD4 T-cell activation, while cDC1s excel in the ability to cross-present cell-associated antigens for CD8 T-cell activation (gray). Upon activation, pDCs also acquire the transcriptional, phenotypic, and functional features of antigen-presenting cells. However, their ability to contribute to the antigen-specific activation of T cells in vivo is controversial. The expression of selected cell surface, cytoplasmic and endosomal molecules, as well as some of the key nuclear transcription factors controlling their development or functions, is shown for each DC type. Molecules exclusively expressed in mice or in humans are depicted in yellow or blue, respectively, while molecules conserved between the two species are in green. The color intensity is proportional to the level of expression

Fig. 2

Molecular mechanisms of viral sensing by pDCs. pDCs sense viral nucleic acids through endosomal TLR7 and TLR9, which recognize single-stranded RNA rich in uridine and unmethylated CpG DNA, respectively. When endosomal TLR7/9 interact with their respective ligands, the MYD88-IRF7 signaling pathway is activated. This leads to the recruitment and phosphorylation of the transcription factor interferon regulatory Factor 7 (IRF7), which is translocated to the nucleus, where it induces transcription of the genes encoding IFN-α/β (IFN-Is) and IFN-λ (IFN-IIIs). Different viral recognition mechanisms have been proposed to promote pDC activation and trigger IFN production. Virus-derived nucleic acid contained in exosomes or apoptotic/necrotic bodies released from infected cells can be captured by pDCs and engulfed into endosomes ①. Free viruses can also be captured by pDCs via unknown receptors and activate them ②. Finally, pDCs can establish contact-dependent interactions with infected cells, generating an immune synapse involving adhesion molecules, such as LFA-1, which is expressed by pDCs, and ICAM-1, which is expressed by infected cells ③. The TNFR expressed by pDCs may also stabilize this synapse upon interaction with its ligand TNF, which can be expressed in a membrane-bound form at the surface of infected cells. As another source of TNF, pDCs may also amplify their own IFN production in an autocrine or paracrine response, but other TNF sources may also be involved. The stabilization of the immune synapse requires the polarization of the actin network in pDCs, which enables pDCs to capture viral material, the nature of which has not yet been elucidated and could vary depending on the nature of the virus and the infected cells

Fig. 3

Resident and recruited pDC populations in the whole mouse body. At steady state, pDCs are widely distributed in the body, located in the indicated lymphoid organs (thymus, lymph node, spleen) and nonlymphoid tissues (eyes, liver, spleen and small intestine), as depicted here in mice. However, upon inflammation, pDCs can be recruited to other tissues (e.g., the brain, skin, lungs and large intestine), where their functions differ depending on the pathophysiological context. This knowledge should be extended in the future by performing whole-body cartography of pDC distribution using novel mouse models or tools allowing specific pDC detection in situ

Fig. 4

Immunostimulatory vs. immunoregulatory functions of pDCs. In both lymphoid and nonlymphoid organs, pDCs are involved in various biological and pathological processes in addition to their contribution to antiviral defense. pDCs can exert immunostimulating (IFN production) or immunoregulatory (promotion of Treg cells) functions, which can be beneficial (green) or detrimental (red) for the host, depending on the context. For example, pDCs recruited to the skin upon tissue damage promote tissue repair through IFN production, but when dysregulated, this function can be deleterious, promoting skin pathologies and autoimmune diseases. pDCs might be detrimental in bone marrow thrombocytopenia, by inhibiting proplatelet release due to the pathological loss of SiglecH-dependent inhibition of pDC IFN production. How this process might be beneficial and in what pathophysiological context are unknown. The role of pDCs in the large intestine depends on the pathological context and is still controversial. Immunoregulatory pDCs that produce anti-inflammatory cytokines, such as IL-10 or TGF-β, can benefit the host in different contexts. At a steady state, they can promote the expansion of CD4+ Tregs, contributing to central tolerance in the thymus and to oral tolerance in the liver and small intestine. During neuroinflammation, the recruitment of immunoregulatory pDCs to the brain can dampen inflammatory responses and ameliorate tissue lesions