Dendritic Cells

Abstract

Dendritic cells (DCs) are distributed in almost all tissues body, acting as sentinels of the immune system. They serve as specialised pathogen‐sensing and antigen‐presenting cells that initiate and regulate the immune response. DCs are derived from unique progenitors present in the bone marrow, which seed the tissues where they differentiate into mature DCs. Transcriptomic, phenotypic and functional analyses indicate that human and murine DCs can be divided into three subsets: two subsets of conventional DCs (cDC) named cDC1 and cDC2, and a third lineage of plasmacytoid DCs (pDCs). Each subset is unique and has distinct functional specialisations to control specific T‐cell responses. DCs form a complex cellular network capable of integrating multiple environmental signals and can induce either immunity or tolerance. As a consequence, DCs are suitable candidates for therapeutic intervention in immune‐mediated conditions.

Key Concepts

  • Dendritic cells are a heterogeneous group of specialised pathogen‐sensing and antigen‐presenting cells.
  • They are distributed in almost all tissues and organs, and act as sentinels of the immune system.
  • They are derived from DC‐restricted progenitors present in the bone marrow and arise from a dedicated lineage.
  • They can be grouped into three subsets based on ontogeny and transcription factor dependency: two lineages of conventional DCs named cDC1 and cDC2, as well as a third lineage of plasmacytoid DCs (pDCs).
  • Each subset is unique and has distinct functional specialisations.
  • The cDC1 subset is efficient at cross‐presentation, and elicits Th1 responses.
  • The cDC2 subset is capable of eliciting Th2 and Th17 responses.
  • pDCs produce large amounts of type I interferons to combat viral infections.

Keywords: dendritic cell; conventional dendritic cell; plasmacytoid DC; pDC; development; ontogeny; immune function; immune response; dendritic cell subsets; cDC1; cDC2

Figure 1. Dendritic cells control adaptive immunity. Dendritic cells constantly sample the environment for antigens. They phagocytose exogenous antigens, process and present them on either MHC class I or MHC class II molecules. Upon activation, they migrate to the draining lymph node where they present the processed antigens to either naïve CD8+ or CD4+ T cells. cDC1 is shown to be better than cDC2 at cross‐presentation of antigens to naïve CD8+ T cells and CD4+ T cells via MHC class I and II molecules, respectively. Hence, generating cytotoxic T lymphocytes and inducing Th1 immunity, which are important in the clearance of intracellular viruses and bacteria. On the other hand, cDC2 is better than cDC1 in presentation of processed antigens to naïve CD4+ T cells via MHC class II molecules. This results in the induction of Th2 or Th17 immunity, which is important in the clearance of extracellular pathogens, parasites and allergens. pDCs secrete type I interferons to combat viral infections.
Figure 2. Development of DC subsets. DC development begins in the bone marrow. Haematopoietic stem cells differentiate into monocyte‐macrophage dendritic cell progenitors (MDPs), which have both monocyte and dendritic cells potential. MDPs differentiate into the common dendritic cell progenitors (CDPs), which are committed to the DC lineage and common monocyte progenitor (cMOP) that differentiate into monocytes. Within the CDPs, a proportion of cells are committed towards the pDC lineage, while others differentiate into pre‐DCs, which are committed towards the cDC lineage. Mature pDCs exit the bone marrow and enter the circulation to seed the lymphoid tissues. In mouse, pre‐committed pre‐DCs enter the circulation to seed both lymphoid and non‐lymphoid tissues and differentiate into cDC1 or cDC2 subsets. Whether pre‐committed pre‐DCs exist in humans is still unknown. In humans, circulating pre‐DCs are found in the blood but it is unclear if they are precursors of circulating blood dendritic cells or whether they seed the tissues directly or indirectly via circulating pre‐committed pre‐DCs or blood dendritic cells.
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References

Bachem A, GUttler S, Hartung E, et al. (2010) Superior antigen cross‐presentation and XCR1 expression define human CD11c+CD141+ cells as homologues of mouse CD8+ dendritic cells. Journal of Experimental Medicine 207: 1273–1281.

Bedoui S, Whitney PG, Waithman J, et al. (2009) Cross‐presentation of viral and self antigens by skin‐derived CD103+ dendritic cells. Nature Immunology 10: 488–495.

Belz GT and Nutt SL (2012) Transcriptional programming of the dendritic cell network. Nature Reviews Immunology 12: 101–113.

Bogunovic M, Ginhoux F, Helft J, et al. (2009) Origin of the lamina propria dendritic cell network. Immunity 31: 513–525.

Brasel K, De Smedt T, Smith JL, et al. (2000) Generation of murine dendritic cells from flt3‐ligand‐supplemented bone marrow cultures. Blood 96: 3029–3039.

Breton G, Lee J, Zhou YJ, et al. (2015) Circulating precursors of human CD1c+ and CD141+ dendritic cells. Journal of Experimental Medicine 212: 401–413.

Briseño CG, Murphy TL and Murphy KM (2014) Complementary diversification of dendritic cells and innate lymphoid cells. Current Opinion in Immunology 29: 69–78.

Cella M, Jarrossay D, Facchetti F, et al. (1999) Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nature Medicine 5: 919–923.

Cisse B, Caton ML, Lehner M, et al. (2008) Transcription factor E2‐2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135: 37–48.

Colonna M, Trinchieri G and Liu Y‐J (2004) Plasmacytoid dendritic cells in immunity. Nature Immunology 5: 1219–1226.

Coombes JL, Siddiqui KRR, Arancibia‐Cárcamo CV, et al. (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF‐beta and retinoic acid‐dependent mechanism. Journal of Experimental Medicine 204: 1757–1764.

Crozat K, Guiton R, Contreras V, et al. (2010) The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8alpha+ dendritic cells. Journal of Experimental Medicine 207: 1283–1292.

Desch AN, Randolph GJ, Murphy K, et al. (2011) CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell‐associated antigen. Journal of Experimental Medicine 208: 1789–1797.

Ding Y, Wilkinson A, Idris A, et al. (2014) FLT3‐ligand treatment of humanized mice results in the generation of large numbers of CD141+ and CD1c+ dendritic cells in vivo. Journal of Immunology 192: 1982–1989.

Doulatov S, Notta F, Eppert K, et al. (2010) Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nature Immunology 11: 585–593.

Dutertre C‐A, Wang L‐F and Ginhoux F (2014) Aligning bona fide dendritic cell populations across species. Cellular Immunology 291: 3–10.

Dzionek A, Inagaki Y, Okawa K, et al. (2002) Plasmacytoid dendritic cells: from specific surface markers to specific cellular functions. Human Immunology 63: 1133–1148.

D'Agostino PM, Gottfried‐Blackmore A, Anandasabapathy N, et al. (2012) Brain dendritic cells: biology and pathology. Acta Neuropathologica 124: 599–614.

Fogg DK, Sibon C, Miled C, et al. (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311: 83–87.

Förster R, Davalos‐Misslitz AC and Rot A (2008) CCR7 and its ligands: balancing immunity and tolerance. Nature Reviews Immunology 8: 362–371.

Ginhoux F, Liu K, Helft J, et al. (2009) The origin and development of nonlymphoid tissue CD103+ DCs. Journal of Experimental Medicine 206: 3115–3130.

Ginhoux F and Merad M (2010) Ontogeny and homeostasis of Langerhans cells. Immunology and Cell Biology 88: 387–392.

Grajales‐Reyes GE, Iwata A, Albring J, et al. (2015) Batf3 maintains autoactivation of Irf8 for commitment of a CD8α(+) conventional DC clonogenic progenitor. Nature Immunology 16: 708–717.

Greter M, Helft J, Chow A, et al. (2012) GM‐CSF controls nonlymphoid tissue dendritic cell homeostasis but is dispensable for the differentiation of inflammatory dendritic cells. Immunity 36: 1031–1046.

Grouard G, Rissoan MC, Filgueira L, et al. (1997) The enigmatic plasmacytoid T cells develop into dendritic cells with interleukin (IL)‐3 and CD40‐ligand. Journal of Experimental Medicine 185: 1101–1111.

Guilliams M, Crozat K, Henri S, et al. (2010) Skin‐draining lymph nodes contain dermis‐derived CD103(‐) dendritic cells that constitutively produce retinoic acid and induce Foxp3(+) regulatory T cells. Blood 115: 1958–1968.

Guilliams M, Ginhoux F, Jakubzick C, et al. (2014) Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nature Reviews Immunology 14: 571–578.

den Haan JM, Lehar SM and Bevan MJ (2000) CD8(+) but not CD8(‐) dendritic cells cross‐prime cytotoxic T cells in vivo. Journal of Experimental Medicine 192: 1685–1696.

Hacker C, Kirsch RD, Ju X‐S, et al. (2003) Transcriptional profiling identifies Id2 function in dendritic cell development. Nature Immunology 4: 380–386.

Hambleton S, Salem S, Bustamante J, et al. (2011) IRF8 mutations and human dendritic‐cell immunodeficiency. New England Journal of Medicine 365: 127–138.

Haniffa M, Collin M and Ginhoux F (2013) Ontogeny and functional specialization of dendritic cells in human and mouse. Advances in Immunology 120: 1–49.

Haniffa M, Shin A, Bigley V, et al. (2012) Human tissues contain CD141hi cross‐presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity 37: 60–73.

Hart DN and Fabre JW (1981) Demonstration and characterization of Ia‐positive dendritic cells in the interstitial connective tissues of rat heart and other tissues, but not brain. Journal of Experimental Medicine 154: 347–361.

Helft J, Ginhoux F, Bogunovic M, et al. (2010) Origin and functional heterogeneity of non‐lymphoid tissue dendritic cells in mice. Immunological Reviews 234: 55–75.

Henri S, Poulin LF, Tamoutounour S, et al. (2010) CD207+ CD103+ dermal dendritic cells cross‐present keratinocyte‐derived antigens irrespective of the presence of Langerhans cells. Journal of Experimental Medicine 207: 189–206.

Hettinger J, Richards DM, Hansson J, et al. (2013) Origin of monocytes and macrophages in a committed progenitor. Nature Immunology 14: 821–830.

Hémont C, Neel A, Heslan M, et al. (2013) Human blood mDC subsets exhibit distinct TLR repertoire and responsiveness. Journal of Leukocyte Biology 93: 599–609.

Hoeffel G, Wang Y, Greter M, et al. (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac‐derived macrophages. Journal of Experimental Medicine 209: 1167–1181.

Jackson JT, Hu Y, Liu R, et al. (2011) Id2 expression delineates differential checkpoints in the genetic program of CD8α+ and CD103+ dendritic cell lineages. The EMBO Journal 30: 2690–2704.

Joffre OP, Segura E, Savina A, et al. (2012) Cross‐presentation by dendritic cells. Nature Reviews Immunology 12: 557–569.

Kapsenberg ML (2003) Dendritic‐cell control of pathogen‐driven T‐cell polarization. Nature Reviews Immunology 3: 984–993.

Karsunky H, Merad M, Cozzio A, et al. (2003) Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid‐committed progenitors to Flt3+ dendritic cells in vivo. Journal of Experimental Medicine 198: 305–313.

Lauterbach H, Bathke B, Gilles S, et al. (2010) Mouse CD8alpha+ DCs and human BDCA3+ DCs are major producers of IFN‐lambda in response to poly IC. Journal of Experimental Medicine 207: 2703–2717.

Lee J, Breton G, Aljoufi A, et al. (2015a) Clonal analysis of human dendritic cell progenitor using a stromal cell culture. Journal of Immunological Methods 425: 21–26.

Lee J, Breton G, Oliveira TYK, et al. (2015b) Restricted dendritic cell and monocyte progenitors in human cord blood and bone marrow. Journal of Experimental Medicine 212: 385–399.

León B, Ballesteros‐Tato A and Lund FE (2014) Dendritic cells and B cells: unexpected partners in Th2 development. Journal of Immunology 193: 1531–1537.

Lewis KL, Caton ML, Bogunovic M, et al. (2011) Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35: 780–791.

Liu K, Victora GD, Schwickert TA, et al. (2009) In vivo analysis of dendritic cell development and homeostasis. Science 324: 392–397.

Luber CA, Cox J, Lauterbach H, et al. (2010) Quantitative proteomics reveals subset‐specific viral recognition in dendritic cells. Immunity 32: 279–289.

Münz C (2012) Antigen processing for MHC class II presentation via autophagy. Frontiers in Immunology 3.

Naik SH, Proietto AI, Wilson NS, et al. (2005) Cutting edge: generation of splenic CD8 and CD8‐dendritic cell equivalents in Fms‐like tyrosine kinase 3 ligand bone marrow cultures. Journal of Immunology 174: 6592–6597.

Naik SH, Sathe P, Park H‐Y, et al. (2007) Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nature Immunology 8: 1217–1226.

Onai N, Kurabayashi K, Hosoi‐Amaike M, et al. (2013) A clonogenic progenitor with prominent plasmacytoid dendritic cell developmental potential. Immunity 38: 943–957.

Onai N, Obata‐Onai A, Schmid MA, et al. (2007) Identification of clonogenic common Flt3+M‐CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nature Immunology 8: 1207–1216.

Plantinga M, Guilliams M, Vanheerswynghels M, et al. (2013) Conventional and monocyte‐derived CD11b(+) dendritic cells initiate and maintain T helper 2 cell‐mediated immunity to house dust mite allergen. Immunity 38: 322–335.

Poulin LF, Reyal Y, Uronen‐Hansson H, et al. (2012) DNGR‐1 is a specific and universal marker of mouse and human Batf3‐dependent dendritic cells in lymphoid and nonlymphoid tissues. Blood 119: 6052–6062.

Poulin LF, Salio M, Griessinger E, et al. (2010) Characterization of human DNGR‐1+ BDCA3+ leukocytes as putative equivalents of mouse CD8alpha+ dendritic cells. Journal of Experimental Medicine 207: 1261–1271.

Proietto AI, Mittag D, Roberts AW, et al. (2012) The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34(+) stem cells in the presence of fms‐like tyrosine kinase 3 ligand and thrombopoietin. Cellular and Molecular Immunology 9: 446–454.

Pulendran B, Banchereau J, Burkeholder S, et al. (2000) Flt3‐ligand and granulocyte colony‐stimulating factor mobilize distinct human dendritic cell subsets in vivo. The Journal of Immunology 165: 566–572.

Qiu C‐H, Miyake Y, Kaise H, et al. (2009) Novel subset of CD8{alpha}+ dendritic cells localized in the marginal zone is responsible for tolerance to cell‐associated antigens. Journal of Immunology 182: 4127–4136.

Randolph GJ, Angeli V and Swartz MA (2005) Dendritic‐cell trafficking to lymph nodes through lymphatic vessels. Nature Reviews Immunology 5: 617–628.

Raphael I, Nalawade S, Eagar TN, et al. (2015) T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine 74: 5–17.

Reizis B, Bunin A, Ghosh HS, et al. (2011) Plasmacytoid dendritic cells: recent progress and open questions. Annual Review of Immunology 29: 163–183.

Reynolds G and Haniffa M (2015) Human and mouse mononuclear phagocyte networks: a tale of two species? Frontiers in Immunology 6: 330.

Sallusto F and Lanzavecchia A (2009) Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. European Journal of Immunology 39: 2076–2082.

Schiavoni G, Mattei F, Sestili P, et al. (2002) ICSBP is essential for the development of mouse type I interferon‐producing cells and for the generation and activation of CD8 dendritic cells. Journal of Experimental Medicine 196: 1415–1425.

Schlitzer A, McGovern N and Ginhoux F (2015a) Dendritic cells and monocyte‐derived cells: two complementary and integrated functional systems. Seminars in Cell and Developmental Biology 41: 9–22.

Schlitzer A, McGovern N, Teo P, et al. (2013) IRF4 transcription factor‐dependent CD11b+ dendritic cells in human and mouse control mucosal IL‐17 cytokine responses. Immunity 38: 970–983.

Schlitzer A, Sivakamasundari V, Chen J, et al. (2015b) Identification of cDC1‐ and cDC2‐committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow. Nature Immunology 16: 718–728.

Schuster S, Hurrell B and Tacchini‐Cottier F (2013) Crosstalk between neutrophils and dendritic cells: a context‐dependent process. Journal of Leukocyte Biology 94: 671–675.

Sertl K, Takemura T, Tschachler E, et al. (1986) Dendritic cells with antigen‐presenting capability reside in airway epithelium, lung parenchyma, and visceral pleura. Journal of Experimental Medicine 163: 436–451.

Shortman K and Heath WR (2010) The CD8+ dendritic cell subset. Immunological Reviews 234: 18–31.

Shortman K, Sathe P, Vremec D, et al. (2013) Plasmacytoid dendritic cell development. Advances in Immunology 120: 105–126.

Steinman RM (2012) Decisions about dendritic cells: past, present, and future. Annual Review of Immunology 30: 1–22.

Steinman RM and Cohn ZA (1973) Identification of a novel cell type in peripheral lymphoid organs of mice I. Morphology, quantitation, tissue distribution. Journal of Experimental Medicine 137: 1142–1162.

Tailor P, Tamura T, Morse HC, et al. (2008) The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse. Blood 111: 1942–1945.

Tamoutounour S, Guilliams M, Montanana Sanchis F, et al. (2013) Origins and functional specialization of macrophages and of conventional and monocyte‐derived dendritic cells in mouse skin. Immunity 39: 925–938.

Tussiwand R, Everts B, Grajales‐Reyes GE, et al. (2015) Klf4 expression in conventional dendritic cells is required for T helper 2 cell responses. Immunity 42: 916–928.

Tussiwand R, Lee W‐L, Murphy TL, et al. (2012) Compensatory dendritic cell development mediated by BATF‐IRF interactions. Nature 490: 502–507.

Varol C, Vallon‐Eberhard A, Elinav E, et al. (2009) Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31: 502–512.

Villadangos JA and Schnorrer P (2007) Intrinsic and cooperative antigen‐presenting functions of dendritic‐cell subsets in vivo. Nature Reviews Immunology 7: 543–555.

Waskow C, Liu K, Darrasse‐Jèze G, et al. (2008) The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nature Immunology 9: 676–683.

Watchmaker PB, Lahl K, Lee M, et al. (2014) Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nature Immunology 15: 98–108.

Yamane H and Paul WE (2012) Cytokines of the γ(c) family control CD4+ T cell differentiation and function. Nature Immunology 13: 1037–1044.

Further Reading

Merad M, Ginhoux F and Collin M (2008) Origin, homeostasis and function of Langerhans cells and other langerin‐expressing dendritic cells. Nature Reviews Immunology 8: 935–947.

Mildner A and Jung S (2014) Development and function of dendritic cell subsets. Immunity 40: 642–656.

Mildner A, Yona S and Jung S (2013) A close encounter of the third kind: monocyte‐derived cells. Advances in Immunology 120: 69–103.

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See, Peter, and Ginhoux, Florent(Dec 2015) Dendritic Cells. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001125.pub4]