Although both cDCs and pDCs are derived from BM cells, pDCs can be differentiated from common dendritic cell progenitors (CDPs) via a unique pathway by the constitutive expression of E2-2, which is a pDC-specific transcription factor (19). FLT3-ligand-STAT3 signaling can promote the expression of E2-2 (20). The pDC can be originated from IL-7R⁺ lymphoid precursor cells and the amount of IRF8 is associated with pDC commitment (21). The transcription factor Zeb2 regulates commitment to pDCs by repressing Id2 (2223). The cDC precursors migrate from the BM to lymphatic or peripheral tissues, existing as a resident or migratory DCs. Upon microbial stimuli, these immature cDCs migrate to the LNs to develop activated phenotypes. On the other hand, pDCs are fully developed in the BM and then migrate into the thymus and secondary lymphoid organs via the blood circulation (24). Furthermore, the pDCs migrated from the BM to the small intestine via C-C chemokine receptor type 9 chemokine receptors (25). Several factors including mucosal vascular addressin cell adhesion molecule 1, β7 integrin, and CD103 are also involved in pDC trafficking to the gut (26). The pDCs can act as APCs as well as effector cells that secrete type I and type III IFNs. Once infected, pDCs secrete type I IFN, underwent morphological and functional changes, and then acted as an APC to prime naïve T cells (27). The pDCs selectively express TLR2 (28), TLR7 (29), TLR9 (30), TLR11, and TLR12 (31). The recognition of the microbial pathogen by pDC is mainly mediated by the endosomal sensors TLR7 and TLR9. TLR7 recognizes RNA viruses such as influenza, and TLR9 recognizes unmethylated CpG-rich sequences of DNA viruses such as herpes simplex virus (HSV)-1 and HSV-2 (32). Once recognized via these receptors, pDCs secrete type I IFNs through the myeloid differentiation primary response 88-IRF7 pathway and produce pro-inflammatory cytokines through the NF-κB pathway. The pDCs also detect Toxoplasma gondii profilin (31) and bacterial polysaccharide A (PSA) (28) via TLR12 and TLR2, respectively.

In addition, pDCs can also detect cytosolic DNA by the cyclic GMP-AMP synthase stimulator of interferon genes pathway to induce the production of type I IFN (33). Lastly, pDCs also express various vitamin D receptors, and vitamin D signaling can act as a natural inhibitory mechanism on pDCs (34).

The production of type I IFN from gut pDCs can be affected by the mucosal microenvironment. IL-10 expressed by activated LP DCs and macrophages, prostaglandin E2 (PGE2) by stromal cells, and TGF-β by intestinal epithelial cells can prevent PP pDCs from producing significant amounts of type I IFN by inhibiting primary signaling via TLR9 (17). In fact, the production of type I IFN from the spleen pDCs can be inhibited by IL-10, PGE2, and TGF-β in response to a treatment of CpG oligodeoxynucleotides. Furthermore, pDCs are generally resident DC subsets in the gut (35). However, pDCs can mobilize LP cDCs to the MLNs in response to TLR stimuli via TNF and type I IFN-dependent mechanisms (36).

Gut pDCs are known for the induction of oral tolerance (18) rather than the production of type I IFN (17). Mucosal factors that are expressed from GALT can inhibit type I IFN secretion by pDCs, while maintaining the ability of pDCs to prime naive T cells and triggering differentiation into Tregs (37) and Th17 cells (38). Gut pDCs are effective in causing mucosal B cell responses to induce IgA production independently of T cells (39). As studies regarding the interaction between the mucosal immune system and microbiome are rapidly progressing, pDCs in GALT are also becoming the focus of increasing interest (32). The roles of gut pDCs are summarized in Fig. 1.

The interactions between ILCs and pDCs in healthy and diseased guts have not been well characterized yet. The ILC family includes classic cytotoxic NK cells as well as non-cytotoxic ILC populations consisting of 3 distinct groups (40). The distribution of human ILC subsets varies in tissues and organs (41). Group 1 ILCs, including NK cells, mostly exist in the fetal intestine and liver. ILC2s are founded in the peripheral blood, lung, and skin. ILC3s are mainly in the skin tissue, thymus, tonsils, BM, and intestine (40). Both cDCs and pDCs can activate NK cells but stimulate different functions of NK cells (42). The cDCs primarily activate NK cells to secrete IFN-γ via the production of IL-12 and IL-18, and to proliferate and survive via the production of IL-15. In contrast, pDCs trigger NK cell cytotoxicity by type I IFN (43). The production of type I IFN from pDCs can be inhibited by activating the NK cell receptor natural cytotoxicity triggering receptor 2 (44), or activated by the inhibitory NK cell receptor IRp60 (45). The ILC2 populations are low in the intestine but prevalent in the lung (40). In the lung, activation of pDCs through TLR7 suppresses ILC2-mediated airway hyper-reactivity and airway inflammation, since IFN-α increased ILC2 apoptosis (46). ILC3s play critical roles in mucosal homeostasis and gut immunity. Gut-resident ILC3s can produce IL-22 that was essential for gut barrier function (4748). In HIV-1 infections, pDCs can make ILC3s that undergo CD95/FasL-mediated apoptosis via type I IFN (49). Therefore, sustained pDC activation and type I IFN production during chronic viral infection may possibly impair the integrity of the gut mucosal barrier by reducing intestinal ILC3 cells (50).

Immune tolerance is an important process in the gut because oral tolerance discriminates the latent pathogenic microorganisms from the commensal flora. Failure of oral tolerance may induce mucosal inflammation, resulting in diseases such as inflammatory bowel diseases (IBDs) and food allergies. Gut pDCs have a tendency to induce the differentiation of CD4⁺Foxp3⁺ Tregs instead of CD4⁺ effector T cells via autocrine TGF-β (37). Systemic depletion of pDCs prevents induction of oral tolerance by Ag feeding (18). Unlike cDCs, pDCs are inefficient for phagocytosis and the presentation of exogenous Ags to CD4⁺ T cells because of the sustained MHC class II-peptide complex formation, ubiquitination, and turnover (51). Although pDCs are less efficient for induction of T cells compared to cDCs, they could still activate CD4⁺ helper and Tregs, as well as CD8⁺ cytotoxic T cells (5253). In response to TLR stimulation, pDCs promote efficient Th17 differentiation (54). In humans, pDCs are inefficient for the activation of Tregs, but are efficient for the induction of effector T cells and support Th17 cell effector function (5556). T cells that are primed by CD40L-activated pDCs have regulatory phenotypes, resulting in decreased IL-2 and IFN-γ production and increased IL-10 (16). The pDCs exposed to PSA from gut commensal Bacterioides fragilis do not produce proinflammatory cytokines, but instead they specifically stimulated IL-10 secretion by CD4⁺ T cells (28). PSA preferentially ligated to TLR2 on pDCs but not on other DC subsets. Ligation of PSA on pDCs cannot directly produce IL-10. Direct secretion of IL-10 by pDCs is dependent on TLR-9, while IL-10 secretion by myeloid DCs is dependent on TLR-2/6 (57). Furthermore, pDCs express indoleamine 2,3 dioxygenase (IDO), which is the rate-limiting step for the degradation of tryptophan into kynurenine and downstream products along the kynurenine pathway (58). IDO is essential for Treg generation by pDCs (59). Interactions of microbiota and pDCs are involved in the regulation of inflammation (60). Feeding of probiotic Bifidobacterium adolescentis increases pDCs and Treg frequencies as well as immunity towards pathogenic infections with Yersinia enterocolitica (61). Probiotic Lactobacillus gasseri increases the population of pDCs that can activate Tregs (62).

Secretory IgA is continuously produced from the mucosal surface, which forms the first-line barrier along with the mucus to protect the mucosal surface by inhibiting attaching microbes and neutralizing toxic materials (63). B cells undergo a class-switching recombination (CSR) process to produce IgA via T cell-dependent (TD) or T cell-independent (TI) pathways mainly in the PPs as well as the LP including the ILFs (6465). The pDCs from the MLN and PP induce a significantly higher production of TI IgA CSR by B cells compared to MLN and PP cDCs (39). However, there is minimal IgA production in pDCs isolated from the peripheral LN. The microbiota activates stromal cells to produce type I IFNs that drove the pDCs to express B cell activating factor and a proliferation-inducing ligand, thereby facilitating IgA responses in the gut. However, a recent study suggests that pDCs are not critical for non-infectious IgA responses (66). Overall, these studies suggest that various gut DC subsets including pDCs may play redundant roles in intestinal IgA homeostasis.

The pDCs recognize pathogens by microbial nucleic acids via TLR7 or TLR9, then produce large quantities of type I IFN. The production of type I IFN by pDC can be an important key step to protect against viral infections in the acute phase (16). The role of pDCs in enteric rotavirus infections has been relatively well studied. Rotavirus is a common pathogenic virus in children under the age of 5 years and is replicated mainly in small intestinal epithelial cells (67). Recognition of viral dsRNA or DNA by the endosomal receptor TLR7 or TLR9 is important for the production of IFN-α from pDCs. During a rotavirus infection, pDCs play a role in the activation of GALT B cells via type I IFNs (68). However, in some cases such as influenza infections, pDCs cause uncontrolled inflammation or bronchial epithelium apoptosis (69). The activation of pDCs in acute viral infections may induce different results depending on the type of virus and the route of infection (32). The role of pDCs in controlling chronic viral infections also differs depending on the type of virus. Although the level of type I IFN induced by infection of hepatitis B virus, hepatitis C virus, and human papilloma virus is low, type I IFNs appear to play an important role in the control of virus and the survival of anti-viral T cells (70). In human patients with HIV, pDCs are depleted in the circulation but accumulated in the terminal ileum showing upregulation of gut-homing receptor CD103 (71). Excessive production of IFN-α by pDCs is a typical phenomenon of HIV infection. The pDCs can induce T cell apoptosis and promote Treg development (72). In addition to T cells, pDCs can upregulate CD95 expression on ILC3s via type I IFN to induce CD95/FasL-mediated apoptosis (49).

Although pDCs have been shown to play a role in viral infections, the role of pDCs has not been well studied in bacterial infections. The pDCs in the MLN and spleen are expanded after intragastric infection of Listeria monocytogenes, which is a gram-positive intracellular bacterium causing severe food-borne gastroenteritis (73). The increased number of pDCs lasts up to 12 days after infection, in which no bacteria were detected, and returns to the basal level at day 19 of infection. In addition, the expressions of costimulatory molecules on pDCs are upregulated, contributing to interactions with T cell. The pDCs in the colon-draining LNs during a Citrobacter rodentium infection can be specifically activated, resulting in the production of C-type lectin receptor and proinflammatory cytokines (74).

IBDs, which includes ulcerative colitis (UC) and Crohn's disease, are chronic inflammatory diseases due to microbial violation or mucosal barrier insults mainly observed in genetically susceptible individuals (75). In patients with IBDs, pDCs significantly accumulate in the MLN and inflamed colonic mucosa. However, the secretion of IFN-α from peripheral blood pDCs in patients with flaring UC is significantly reduced, suggesting their role as tolerance inducers (76). The roles of pDCs and type I IFN have more complicated features in gut inflammation. In an acute colitis model by a single-cycle administration of dextran sulfate sodium, pDCs accumulate in inflamed areas of acute colitis (77). Selective depletion of pDCs in the pDC-ablated mice that expressed DTR under the control of the Siglec-H gene attenuates acute colitis by decreasing infiltration of inflammatory leukocytes and production of proinflammatory cytokines independent of IFN-I signaling (77). When pDCs are depleted by targeting E2-2, the pDC-specific transcription factor, pDCs are dispensable for the pathogenesis of intestinal inflammation in the experimental IBD model caused by a deficiency of the Wiskott-Aldrich syndrome protein or IL-10 (78). In contrast, several reports support the regulatory roles that type I IFN plays in intestinal injury and inflammation. GM-CSF can ameliorate colitis by increasing type I IFN production of pDC (79). Activation of TLR3 and TLR9 protects mice from experimental colitis via induction of type I IFN (8081). Recognition of gut resident RNA viruses through TLR3 and TLR7 can regulate acute colitis via IFN-β secretion from pDCs (82). Furthermore, anti-viral drug cocktail treatments exacerbate gut inflammation. In fact, the gut virome exhibits different patterns in patients with IBD compared to healthy individuals, suggesting that the enteric virome may play a role in intestinal diseases (83). Collectively, although the role of pDCs in the intestinal inflammatory disease is controversial, pDCs have a role in gut immune homeostasis by managing the inflammatory or anti-inflammatory response in a case-dependent manner.

The recruitment of pDCs in peri-tumor sites is often associated with poor prognosis (Fig. 2A) since the tumor microenvironment converted pDCs into immunosuppressive cells (84). Tumor-derived TGF-β and TNF-α inhibit the production of IFN-α by tumor-associated pDCs (8586). Tumor-infiltrating pDCs tend to induce Treg cells through the expression of IDO (59) or inducible co-stimulatory receptor ligand (87). Within tumor draining LNs, a small population of IDO⁺ pDCs also creates a suppressive microenvironment via constitutive activation of Tregs (88). Human CD123⁺ pDCs in colorectal tumor tissue and LNs may help developing Tregs and foster tumor tolerance (89). In patients with colorectal cancer, the frequency of pDCs is low, and they tend to be functionally defective (90). The pDCs are also involved in cancer progression via expression of pro-apoptotic granzyme B, which inhibits the proliferation of anti-tumor T cells (91). In contrast to NK cells, pDCs do not release the pore-forming perforin. In tumor-draining LNs, pDCs constitutively express immunosuppressive IDO enzyme (92). The lymphocyte-activation gene 3⁺ pDCs in melanoma produce IL-6 without induction of type I IFN. IL-6 induce the production of CCL2 that can recruit myeloid-derived suppressor cells (MDSCs) at the tumor tissue (93). The number of pDCs in blood is variable depending on the type and progressions of cancer. In patients with melanoma, circulating pDCs are significantly decreased (90). The decrease of circulating pDCs correlates to a more advanced stage of cancer progress, and recovers after complete tumor resection. In gastric carcinoma tissue, Tregs and inducible co-stimulatory receptor (ICOS)⁺ Tregs are the main lineage cells, whereas pDCs are the majority in peri-tumor tissue (94). Under gastric tumor conditions, pDCs may recruit ICOS⁺ Tregs and act as immunosuppressants. Tumor-associated pDCs are poor producers of type I IFN and favor the IL-10 induction from increased Tregs in breast (85) and ovarian cancers (95).

When properly reprogrammed by stimuli such as TLR agonists, tumor promotion by peri- or intra-tumoral pDCs can be reversed (Fig. 2B), which can further mediate tumor rejection in a clinical setting (96). Tumor regression can be driven by restored production of type I IFN along with a cross-talk with other immune cells. Finally, pDCs can act as an APC to prime anti-tumor T cells. The pDCs isolated from human colon carcinomas have epithelial cell adhesion molecules (97). Despite deficiencies in phagocytosis, there exists an alternative mechanism of exchange for exogenous Ags between pDCs and tumor cells, which is a cell contact-dependent mechanism. This may enable pDCs to present Ag to tumor Ag-specific T cells. Furthermore, the pDCs can regulate myelopoiesis, especially CD11b^highGr-1⁺ MDSCs in the BM (98). When pDCs are activated by TLR9 stimulation, the production of IFN-α induces MDSC maturation and then blocks MDSC suppressive capacity (99). Activated pDCs can exert direct cytotoxicity to tumor cells by expression of TNF-related apoptosis inducing ligand and granzyme B (100). Alternatively, activated pDCs stimulate NK cells to kill tumor cells (101). Although still limited to several types of cancers besides colon cancer, modulation of pDCs by TLR ligand treatment can be a promising strategy for cancer immunotherapy.