Fig 1.
Development of DCs as an independent cell lineage showing transcriptional regulation, expression of prominent surface markers, and their functional characteristics. The illustration shows how common progenitors give rise to distinct fractions of DCs, monocytes, and macrophages. MPPs, which are produced from HSCs, go through stages of differentiation to create lineage-restricted progenitors of lymphocytes and myeloid cells, called CMPs. The CMPs are separated into two subsets such as MDPs and GMPs on the basis of Cbfb and Cebpa expression. Based on GFI1 expression, GMPs are divided into two subsets such as cMoPs and granulocyte progenitors. The cMoPs further give rise to LCs, MoDCs, and macrophages, potentially based on the expression of RUNX3, ID-2, IRF8 and IRF4 and ZEB2 expression, respectively. The specification of cDC1s and pDCs is correlated with a high level of IRF8 expression from MDPs. On the other hand, cDC2s are correlated with a high level of IRF4 expression. cDC1s, type 1 conventional DCs; cDC2s, type 2 conventional DCs; cDCs, conventional DC; cDPs, common dendritic cell progenitors; cMoPs, common monocyte progenitor; CMPs, common myeloid progenitors; DCs, dendritic cells; FLT3L, FAM-like tyrosine kinase 3 ligand; GMP, granulocyte-macrophage progenitor; HSCs, hematopoietic stem cells; IFN-α, interferon-α; IFN-β, interferon-β; IL-6, interleukin-6; LCs, Langerhans cells; MDPs, monocyte and dendritic cell progenitors; MoDCs, monocyte derived dendritic cells; MPPs, multipotent progenitors; pDCs, plasmacytoid DCs; TF, transcription factor.
Table 1.
miRNA influencing DCs development
| miRNA | Target | Role | References |
|---|---|---|---|
| miRNA-520h | ABCG2 | HSCs differentiation | Liao et al. (2008) |
| miRNA-129 | CAMTA1, EIF2C3 | HSCs differentiation | Liao et al. (2008) |
| miRNA-125b | BMF and KLF13 | HSCs survival and growth | Ooi et al. (2010) |
| miRNA-142 | FLT3 | Differentiation, development, maintenance of CD4+ DCs | Mildner et al. (2013a) |
| miRNA-146a | IRAK1, NFKB | pDCs survival | Karrich et al. (2013) |
[i] ABCG2, ATP-binding cassette subfamily G member 2; BMF, Bcl2 modifying factor; CAMTA1, Calmodulin-binding transcription activator 1; DCs, dendritic cells; EIF2C3, Eukaryotic translation initiation factor 2C, 3; FLT3, FAM-like tyrosine kinase 3; HSCs, Hematopoietic stem cells; IRAK1, IL-1 receptor-associated kinase 1; KLF13, Krueppel-like factor 13; miRNA, microRNA; NFKB, TLR-induced nuclear factor-kB; pDCs, plasmacytoid DCs.
Table 2.
DC subsets and their surface markers, and TFs regulating their differentiation and function
| Subsets | Surface markers | TF regulating differentiation | Function | References |
|---|---|---|---|---|
| pDCs | CD11clow, SIGLECH+, CD135+, CD4hi, MHC-IIlow, LY6C+, B220+, PDCA-1+, DNGR-1low, IRF8hi, and IL3Rhi | TCF4, BCL11a, RUNX1, SPIB, and IRF-8 | Mediate antiviral immune response, autoimmune disease, and secrete type-1 interferons (IFN-α, IFN-β) and IL-6 | Shortman et al. (2013), Poltorak and Schraml (2015), Tian et al. (2017), and Anderson et al. (2021) |
| cDC1 | CD11c+, MHC-II+, CD135+, CD24+, ZBTB46+, CD8α±, CD205+, XCR1+, and DNGR-1+ | ID-2, BATF3, IRF8, and NFIL3 | Cross-present exogenous antigen to CD8+ CTLs | Shortman and Naik (2007), Poltorak and Schraml (2015), Pakalniškytė and Schraml (2017), Tian et al. (2017), and Anderson et al. (2021) |
| cDC2 | CD11b+, MHC-II+, CD135+, ZBTB46+, CD24±, IRF4hi, and CD8α | IRF4, RELB, RBPT, PU.1, NOTCH2, and KLF4 | Heterogeneous in function (promotes Th17 differentiation in lungs and intestine/Th2 response against viral infections). | Shortman and Naik (2007), Poltorak and Schraml (2015), Pakalniškytė and Schraml (2017), Tian et al. (2017), Anderson et al. (2021), and Wei et al. (2021) |
| MoDCs | MS4a3+, CD11chi, CD40low, CD80/86low, and HLA-DR+ | IRF4 | Facilitates cDC1 to fight against infections and inflammation | Domínguez and Ardavín (2010), Poltorak and Schraml (2015), Tian et al. (2017), Tang-Huau and Segura (2019), and Anderson et al. (2021) |
| LCs | MAFB+, CD1a+, and CD207+ | RUNX3, ID2, and IRF8 | Induce humoral immunity and present antigens to T cells | Kaplan (2010), Poltorak and Schraml (2015), Collin and Milne (2016), Tian et al. (2017), and Anderson et al. (2021) |
| mDCs | CD83+, CD80hi, CD40hi, and MHC-II+, | ND | Produce IFN-γ, TNF-γ, and IL-15. Promote low NK cell proliferation | Peters et al. (1993), Lutz and Schuler (2002), Jeras et al. (2005), Bachy et al. (2008), and Hopkins and Connolly (2012) |
| imDCs | CD83−, SIGN+, CD209+ | ND | Promote angiogenesis and tolerogenic environment in decidua | Gardner and Moffett (2003), Kämmerer et al. (2003), and Kwan et al. (2014) |
| Circulatory DCs | ND | ND | Present antigens to T cells and induce humoral response | Merad et al. (2013) and Boltjes and Van Wijk (2014) |
| Migratory DCs | ND | ND | Present antigens to T cells | Broggi et al. (2013) |
| Resident DCs | ND | ND | Promote negative selection of T cells and present antigens to CD4+ T cells | Taglauer et al. (2010) and Zhou and Wu (2017) |
| Tolerogenic DCs | CD80+, and CD86+ | ND | Induce tolerance, Treg differentiation, and reduce T cell proliferation | Smits et al. (2005) and Hubo et al. (2013), Domogalla et al. (2017), and Takenaka and Quintana (2017) |
| Inflammatory DCs | HLA-DRhi, CD11chi, BDCA1+, CD1a+, CD14+, CD172a+, MHC-IIhi, LY6C, FCERI, CD64+, CD107b, CD115, F4/80+ | CCR2, and GM-CSF | Secrete IL-12, -23, -1a, and -1b, which in turn induce Th1 and Th2 response; play critical role in microbial infections | Butts et al. (2007), Poltorak and Schraml. (2015), and Balan et al. (2019) |
[i] CCR2, C–C motif chemokine receptor 2; cDC, conventional DC; CTLs, cytotoxic T lymphocytes; DCs, dendritic cells; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN-α, interferons-α, IFN-β, interferons-β; IFN-γ, interferons-γ; IL-15, interleukin-15; imDCs, immature DCs; LCs, Langerhans cells; mDCs, matured DCs; MHC-II, major histocompatibility complex class II; moDCs, Monocyte-derived DCs; ND, not defined; NK, natural killer, pDCs, plasmacytoid DCs; TFs, transcription factors, TNF-γ, tumor necrosis factor-γ.
Fig 2.
Flowchart illustrating the regulation of immune responses to the conceptus by DCs. During a typical pregnancy, tolerogenic stimuli such as trophoblasts, progesterone, PGE2, vitamin D, and environmental cells (such as NK cells and Mϕs) encourage partial activation of the local DC. As a result, anti-inflammatory cytokines (like IL-10) are produced, which encourages the induction of tolerance at the maternal–fetal interface by activating a number of mechanisms like the production of pregnancy-protective Th2/Th3 cytokines and the development of Treg cells, which improve immune system suppression and thereby support fetal tolerance. DC, dendritic cell; imDCs: immature DCs; MHC-II, major histocompatibility complex class II; NK, natural killer; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β.
Supplementary Table 1.
Different human DC phenotypes during pregnancy.
Supplementary Table 2.
Different mouse DC phenotypes during pregnancy.