Key Points
-
Dendritic cells (DCs) show extensive subset heterogeneity and functional diversity, and the major functional DC subsets are conserved between humans and mice.
-
DCs contribute to both central and peripheral tolerance, but are not strictly required for either. A mere change in DC numbers, including after constitutive DC ablation, does not cause overt autoimmunity per se.
-
Aberrant activation of DCs is sufficient to cause autoimmunity and/or chronic inflammation. Multiple negative regulators prevent DC activation and autoimmunity in a cell-intrinsic manner.
-
DCs promote the priming and effector differentiation of self-reactive T cells in several experimental autoimmune diseases, including type 1 diabetes and experimental autoimmune encephalomyelitis (EAE).
-
Conversely, antigen presentation by DCs can promote regulatory T cell induction and reduce inflammation in some models, including in EAE.
-
The secretion of type I interferon by plasmacytoid DCs in response to self-nucleic acid might be a common mechanism that leads to pathogenesis in several autoimmune diseases, including in psoriasis, type 1 diabetes and systemic lupus erythematosus.
Abstract
Dendritic cells (DCs) initiate and shape both the innate and adaptive immune responses. Accordingly, recent evidence from clinical studies and experimental models implicates DCs in the pathogenesis of most autoimmune diseases. However, fundamental questions remain unanswered concerning the actual roles of DCs in autoimmunity, both in general and, in particular, in specific diseases. In this Review, we discuss the proposed roles of DCs in immunological tolerance, the effect of the gain or loss of DCs on autoimmunity and DC-intrinsic molecular regulators that help to prevent the development of autoimmunity. We also review the emerging roles of DCs in several autoimmune diseases, including autoimmune myocarditis, multiple sclerosis, psoriasis, type 1 diabetes and systemic lupus erythematosus.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Steinman, R. M. Decisions about dendritic cells: past, present, and future. Annu. Rev. Immunol. 30, 1–22 (2012).
Hashimoto, D., Miller, J. & Merad, M. Dendritic cell and macrophage heterogeneity in vivo. Immunity 35, 323–335 (2011).
Satpathy, A. T., Wu, X., Albring, J. C. & Murphy, K. M. Re(de)fining the dendritic cell lineage. Nature Immunol. 13, 1145–1154 (2012).
Lewis, K. L. & Reizis, B. Dendritic cells: arbiters of immunity and immunological tolerance. Cold Spring Harb. Perspect. Biol. 4, a007401 (2012).
Collin, M., Bigley, V., Haniffa, M. & Hambleton, S. Human dendritic cell deficiency: the missing ID? Nature Rev. Immunol. 11, 575–583 (2011).
Segura, E. et al. Human inflammatory dendritic cells induce Th17 cell differentiation. Immunity 38, 336–348 (2013).
Segura, E. et al. Characterization of resident and migratory dendritic cells in human lymph nodes. J. Exp. Med. 209, 653–660 (2012).
Olsson, T., Holmdahl, R., Klareskog, L. & Forsum, U. Ia-expressing cells and T lymphocytes of different subsets in peripheral nerve tissue during experimental allergic neuritis in Lewis rats. Scand. J. Immunol. 18, 339–343 (1983).
Knight, S. C., Mertin, J., Stackpoole, A. & Clark, J. Induction of immune responses in vivo with small numbers of veiled (dendritic) cells. Proc. Natl Acad. Sci. USA 80, 6032–6035 (1983). This paper shows that 'veiled cells' (that is, DCs) from animals with EAE could transfer the disease to naive recipients, which establishes the capacity of DCs to prime autoreactive T cell responses.
Gallegos, A. M. & Bevan, M. J. Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J. Exp. Med. 200, 1039–1049 (2004).
Hubert, F. X. et al. Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance. Blood 118, 2462–2472 (2011).
Lei, Y. et al. Aire-dependent production of XCL1 mediates medullary accumulation of thymic dendritic cells and contributes to regulatory T cell development. J. Exp. Med. 208, 383–394 (2011).
Klein, L., Hinterberger, M., von Rohrscheidt, J. & Aichinger, M. Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance. Trends Immunol. 32, 188–193 (2011).
Birnberg, T. et al. Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome. Immunity 29, 986–997 (2008). This paper shows that the constitutive ablation of cDCs does not breach central or peripheral tolerance or induce overt autoimmunity.
Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nature Immunol. 7, 1092–1100 (2006).
Proietto, A. I. et al. Dendritic cells in the thymus contribute to T-regulatory cell induction. Proc. Natl Acad. Sci. USA 105, 19869–19874 (2008).
Hawiger, D. et al. Dendritic cells induce peripheral T cell unresponsiveness under steady state conditions in vivo. J. Exp. Med. 194, 769–779 (2001). This study pioneered antibody-mediated antigen targeting to demonstrate the capacity of DCs to induce peripheral T cell tolerance.
Hawiger, D., Masilamani, R. F., Bettelli, E., Kuchroo, V. K. & Nussenzweig, M. C. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity 20, 695–705 (2004).
Probst, H. C., Lagnel, J., Kollias, G. & van den Broek, M. Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity 18, 713–720 (2003). This paper further shows the tolerogenic capacity of DCs in the steady state by genetically targeting antigens to DCs.
Probst, H. C., McCoy, K., Okazaki, T., Honjo, T. & van den Broek, M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nature Immunol. 6, 280–286 (2005).
Muth, S., Schutze, K., Schild, H. & Probst, H. C. Release of dendritic cells from cognate CD4+ T-cell recognition results in impaired peripheral tolerance and fatal cytotoxic T-cell mediated autoimmunity. Proc. Natl Acad. Sci. USA 109, 9059–9064 (2012).
Yamazaki, S. et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J. Exp. Med. 198, 235–247 (2003).
Sela, U., Olds, P., Park, A., Schlesinger, S. J. & Steinman, R. M. Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice. J. Exp. Med. 208, 2489–2496 (2011).
Suffner, J. et al. Dendritic cells support homeostatic expansion of Foxp3+ regulatory T cells in Foxp3. LuciDTR mice. J. Immunol. 184, 1810–1820 (2010).
Bar-On, L., Birnberg, T., Kim, K. W. & Jung, S. Dendritic cell-restricted CD80/86 deficiency results in peripheral regulatory T-cell reduction but is not associated with lymphocyte hyperactivation. Eur. J. Immunol. 41, 291–298 (2011).
Vitali, C. et al. Migratory, and not lymphoid-resident, dendritic cells maintain peripheral self-tolerance and prevent autoimmunity via induction of iTreg cells. Blood 120, 1237–1245 (2012).
Darrasse-Jeze, G. et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J. Exp. Med. 206, 1853–1862 (2009).
Swee, L. K., Bosco, N., Malissen, B., Ceredig, R. & Rolink, A. Expansion of peripheral naturally occurring T regulatory cells by Fms-like tyrosine kinase 3 ligand treatment. Blood 113, 6277–6287 (2009).
Collins, C. B. et al. Flt3 ligand expands CD103+ dendritic cells and FoxP3+ T regulatory cells, and attenuates Crohn's-like murine ileitis. Gut 61, 1154–1162 (2011).
Kriegel, M. A., Rathinam, C. & Flavell, R. A. Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c+ CD11b+ dendritic cells. Proc. Natl Acad. Sci. USA 109, 3457–3462 (2012).
Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010).
Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780–791 (2011).
Zangi, L. et al. Deletion of cognate CD8 T cells by immature dendritic cells: a novel role for perforin, granzyme A, TREM-1, and TLR7. Blood 120, 1647–1657 (2012).
Ohnmacht, C. et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J. Exp. Med. 206, 549–559 (2009).
Teichmann, L. L. et al. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity 33, 967–978 (2010).
Cervantes-Barragan, L. et al. Plasmacytoid dendritic cells control T-cell response to chronic viral infection. Proc. Natl Acad. Sci. USA 109, 3012–3017 (2012).
Chen, M. et al. Dendritic cell apoptosis in the maintenance of immune tolerance. Science 311, 1160–1164 (2006).
Stranges, P. B. et al. Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity. Immunity 26, 629–641 (2007).
Chen, M., Felix, K. & Wang, J. Immune regulation through mitochondrion-dependent dendritic cell death induced by T regulatory cells. J. Immunol. 187, 5684–5692 (2011).
Travis, M. A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).
Melillo, J. A. et al. Dendritic cell (DC)-specific targeting reveals Stat3 as a negative regulator of DC function. J. Immunol. 184, 2638–2645 (2010).
Kim, S. J., Zou, Y. R., Goldstein, J., Reizis, B. & Diamond, B. Tolerogenic function of Blimp-1 in dendritic cells. J. Exp. Med. 208, 2193–2199 (2011).
Hammer, G. E. et al. Expression of A20 by dendritic cells preserves immune homeostasis and prevents colitis and spondyloarthritis. Nature Immunol. 12, 1184–1193 (2011).
Kool, M. et al. The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity. Immunity 35, 82–96 (2011).
Kaneko, T. et al. Dendritic cell-specific ablation of the protein tyrosine phosphatase Shp1 promotes Th1 cell differentiation and induces autoimmunity. J. Immunol. 188, 5397–5407 (2012).
Abram, C. L., Roberge, G. L., Pao, L. I., Neel, B. G. & Lowell, C. A. Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity 38, 489–501 (2013).
Eriksson, U. et al. Dendritic cell-induced autoimmune heart failure requires cooperation between adaptive and innate immunity. Nature Med. 9, 1484–1490 (2003).
Eriksson, U. et al. Activation of dendritic cells through the interleukin 1 receptor 1 is critical for the induction of autoimmune myocarditis. J. Exp. Med. 197, 323–331 (2003).
Sonderegger, I. et al. GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J. Exp. Med. 205, 2281–2294 (2008).
Pagni, P. P., Traub, S., Demaria, O., Chasson, L. & Alexopoulou, L. Contribution of TLR7 and TLR9 signaling to the susceptibility of MyD88-deficient mice to myocarditis. Autoimmunity 43, 275–287 (2010).
Popovic, Z. V. et al. The proteoglycan biglycan enhances antigen-specific T cell activation potentially via MyD88 and TRIF pathways and triggers autoimmune perimyocarditis. J. Immunol. 187, 6217–6226 (2011).
McMahon, E. J., Bailey, S. L., Castenada, C. V., Waldner, H. & Miller, S. D. Epitope spreading initiates in the CNS in two mouse models of multiple sclerosis. Nature Med. 11, 335–339 (2005).
Greter, M. et al. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Med. 11, 328–334 (2005).
Wu, G. F. et al. Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity. J. Autoimmun. 36, 56–64 (2011).
Yogev, N. et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor+ regulatory T cells. Immunity 37, 264–275 (2012). This paper shows the overall anti-inflammatory role of cDCs in EAE using various DC ablation methods.
Isaksson, M., Lundgren, B. A., Ahlgren, K. M., Kampe, O. & Lobell, A. Conditional DC depletion does not affect priming of encephalitogenic Th cells in EAE. Eur. J. Immunol. 42, 2555–2563 (2012).
Huang, G. et al. Signaling via the kinase p38α programs dendritic cells to drive TH17 differentiation and autoimmune inflammation. Nature Immunol. 13, 152–161 (2012).
Melton, A. C. et al. Expression of αvβ8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J. Clin. Invest. 120, 4436–4444 (2010).
Laouar, Y. et al. TGF-β signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 105, 10865–10870 (2008).
Xiao, S. et al. Tim-1 stimulation of dendritic cells regulates the balance between effector and regulatory T cells. Eur. J. Immunol. 41, 1539–1549 (2011).
Guo, B., Chang, E. Y. & Cheng, G. The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J. Clin. Invest. 118, 1680–1690 (2008).
Dann, A. et al. Cytosolic RIG-I-like helicases act as negative regulators of sterile inflammation in the CNS. Nature Neurosci. 15, 98–106 (2012).
Yen, J. H., Kong, W. & Ganea, D. IFN-β inhibits dendritic cell migration through STAT-1-mediated transcriptional suppression of CCR7 and matrix metalloproteinase 9. J. Immunol. 184, 3478–3486 (2010).
Anandasabapathy, N. et al. Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain. J. Exp. Med. 208, 1695–1705 (2011).
Prodinger, C. et al. CD11c-expressing cells reside in the juxtavascular parenchyma and extend processes into the glia limitans of the mouse nervous system. Acta Neuropathol. 121, 445–458 (2011).
Bailey, S. L., Schreiner, B., McMahon, E. J. & Miller, S. D. CNS myeloid DCs presenting endogenous myelin peptides 'preferentially' polarize CD4+ TH-17 cells in relapsing EAE. Nature Immunol. 8, 172–180 (2007).
Poppensieker, K. et al. CC chemokine receptor 4 is required for experimental autoimmune encephalomyelitis by regulating GM-CSF and IL-23 production in dendritic cells. Proc. Natl Acad. Sci. USA 109, 3897–3902 (2012).
Codarri, L. et al. RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nature Immunol. 12, 560–567 (2011).
El-Behi, M. et al. The encephalitogenicity of TH17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nature Immunol. 12, 568–575 (2011).
Bailey-Bucktrout, S. L. et al. Cutting edge: central nervous system plasmacytoid dendritic cells regulate the severity of relapsing experimental autoimmune encephalomyelitis. J. Immunol. 180, 6457–6461 (2008).
Irla, M. et al. MHC class II-restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell-mediated autoimmunity. J. Exp. Med. 207, 1891–1905 (2010). Genetic ablation of MHC class II expression specifically in pDCs shows that pDCs might promote T Reg cell development and they might inhibit inflammation in EAE.
Karni, A. et al. Innate immunity in multiple sclerosis: myeloid dendritic cells in secondary progressive multiple sclerosis are activated and drive a proinflammatory immune response. J. Immunol. 177, 4196–4202 (2006).
Cai, Y. et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity 35, 596–610 (2011).
Pantelyushin, S. et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J. Clin. Invest. 122, 2252–2256 (2012).
van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J. Immunol. 182, 5836–5845 (2009).
Walter, A. et al. Aldara activates TLR7-independent immune defence. Nature Commun. 4, 1560 (2013).
Tortola, L. et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J. Clin. Invest. 122, 3965–3976 (2012).
Nestle, F. O. et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-α production. J. Exp. Med. 202, 135–143 (2005).
Albanesi, C. et al. Chemerin expression marks early psoriatic skin lesions and correlates with plasmacytoid dendritic cell recruitment. J. Exp. Med. 206, 249–258 (2009).
Guiducci, C. et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J. Exp. Med. 207, 2931–2942 (2010).
Gregorio, J. et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J. Exp. Med. 207, 2921–2930 (2010).
Lande, R. et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449, 564–569 (2007).
Ganguly, D. et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J. Exp. Med. 206, 1983–1994 (2009).
de Jersey, J. et al. β-cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 104, 1295–1300 (2007).
Turley, S., Poirot, L., Hattori, M., Benoist, C. & Mathis, D. Physiological β-cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198, 1527–1537 (2003). This paper established the role of DCs in the presentation of β-islet cell antigens to self-reactive T cells in experimental diabetes.
Saxena, V., Ondr, J. K., Magnusen, A. F., Munn, D. H. & Katz, J. D. The countervailing actions of myeloid and plasmacytoid dendritic cells control autoimmune diabetes in the nonobese diabetic mouse. J. Immunol. 179, 5041–5053 (2007).
Calderon, B., Suri, A., Miller, M. J. & Unanue, E. R. Dendritic cells in islets of Langerhans constitutively present β-cell-derived peptides bound to their class II MHC molecules. Proc. Natl Acad. Sci. USA 105, 6121–6126 (2008).
Han, J. et al. Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice. Diabetes 57, 2118–2127 (2008).
Kim, H. S. et al. Toll-like receptor 2 senses β-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27, 321–333 (2007).
Lee, L. F. et al. The role of TNF-α in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: analysis of dendritic cell maturation. Proc. Natl Acad. Sci. USA 102, 15995–16000 (2005).
Van Belle, T. L., Nierkens, S., Arens, R. & von Herrath, M. G. Interleukin-21 receptor-mediated signals control autoreactive T cell infiltration in pancreatic islets. Immunity 36, 1060–1072 (2012).
Huang, X., Hultgren, B., Dybdal, N. & Stewart, T. A. Islet expression of interferon-α precedes diabetes in both the BB rat and streptozotocin-treated mice. Immunity 1, 469–478 (1994).
Huang, X. et al. Interferon expression in the pancreases of patients with type I diabetes. Diabetes 44, 658–664 (1995).
Li, Q. et al. Interferon-α initiates type 1 diabetes in nonobese diabetic mice. Proc. Natl Acad. Sci. USA 105, 12439–12444 (2008).
Diana, J. et al. Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nature Med. 19, 65–73 (2013).
Allen, J. S. et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture. Diabetes 58, 138–145 (2009).
Chilton, P. M. et al. Flt3-ligand treatment prevents diabetes in NOD mice. Diabetes 53, 1995–2002 (2004).
O'Keeffe, M. et al. Fms-like tyrosine kinase 3 ligand administration overcomes a genetically determined dendritic cell deficiency in NOD mice and protects against diabetes development. Int. Immunol. 17, 307–314 (2005).
Kared, H. et al. Treatment with granulocyte colony-stimulating factor prevents diabetes in NOD mice by recruiting plasmacytoid dendritic cells and functional CD4+CD25+ regulatory T-cells. Diabetes 54, 78–84 (2005).
Grupillo, M. et al. Essential roles of insulin expression in Aire+ tolerogenic dendritic cells in maintaining peripheral self-tolerance of islet β-cells. Cell. Immunol. 273, 115–123 (2012).
Walsh, E. R. et al. Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell-mediated autoimmunity. Proc. Natl Acad. Sci. USA 109, 16276–16281 (2012).
Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).
Santiago-Raber, M. L. et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J. Exp. Med. 197, 777–788 (2003).
Jorgensen, T. N., Roper, E., Thurman, J. M., Marrack, P. & Kotzin, B. L. Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 x NZW)F(1) mice. Genes Immun. 8, 653–662 (2007).
Ronnblom, L. & Alm, G. V. A pivotal role for the natural interferon-α-producing cells (plasmacytoid dendritic cells) in the pathogenesis of lupus. J. Exp. Med. 194, F59–F63 (2001).
Blomberg, S. et al. Presence of cutaneous interferon-α producing cells in patients with systemic lupus erythematosus. Lupus 10, 484–490 (2001).
Bave, U. et al. Fcγ RIIa is expressed on natural IFN-α-producing cells (plasmacytoid dendritic cells) and is required for the IFN-α production induced by apoptotic cells combined with lupus IgG. J. Immunol. 171, 3296–3302 (2003).
Means, T. K. et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9. J. Clin. Invest. 115, 407–417 (2005).
Tian, J. et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nature Immunol. 8, 487–496 (2007).
Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).
Garcia-Romo, G. S. et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra20 (2011). References 110 and 111 provide evidence that pDC activation by neutrophil-derived self-DNA molecules promotes the development of SLE in humans.
Guiducci, C. et al. TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus. Nature 465, 937–941 (2010).
Lepelletier, Y. et al. Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs). Blood 116, 3389–3397 (2010).
Zhu, X. J., Yang, Z. F., Chen, Y., Wang, J. & Rosmarin, A. G. PU.1 is essential for CD11c expression in CD8+/CD8− lymphoid and monocyte-derived dendritic cells during GM-CSF or FLT3L- induced differentiation. PLoS ONE 7, e52141 (2013).
Caton, M. L., Smith-Raska, M. R. & Reizis, B. Notch-RBP-J signaling controls the homeostasis of CD8− dendritic cells in the spleen. J. Exp. Med. 204, 1653–1664 (2007).
Persson, E. K. et al. IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38, 958–969 (2013).
Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).
Wohn, C. et al. Langerinneg conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. Proc. Natl Acad. Sci. USA 110, 10723–10728 (2013).
Acknowledgements
The authors thank M. Anderson and A. Ma for communicating unpublished results. The authors apologize to many colleagues whose studies could not be cited because of space constraints. B.R. has been supported by the Lupus Research Institute, the New York State Department of Health IDEA award N09G-22 and the US National Institutes of Health grant AI072571; V.S. has been supported by the Cancer Research Institute; D.G. has been supported by the S.L.E. Lupus Foundation, USA; and S.H. has been supported by the Swiss National Science Foundation.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Type I interferon
-
(Type I IFN). A family of cytokines that comprises IFNβ and multiple subtypes of IFNα, which all signal through a common IFNα/β receptor (IFNAR). Type I IFNs are typically induced by viral infection and can confer an antiviral state, growth arrest and/or apoptosis in host cells, as well as being able to recruit and to activate multiple immune cell types.
- Cross-presentation
-
The ability of certain antigen-presenting cells to load peptides that are derived from exogenous antigens on MHC class I molecules. This property is uncommon, as most cells exclusively present peptides from their endogenous proteins on MHC class I molecules. Cross-presentation is essential for the initiation of immune responses to viruses that do not infect antigen-presenting cells.
- DC ablation
-
The process by which denditic cells (DCs) are depleted; for example, using diphtheria toxin expression or administration. Diphtheria toxin or the diphtheria toxin receptor can be specifically expressed in DCs, which facilitates constitutive or diphtheria toxin-inducible DC ablation, respectively. Limitations to this method include the potential depletion of other cell types, the nonspecific toxicity of the administered diphtheria toxin and secondary effects owing to substantial cell death.
- FMS-related tyrosine kinase 3 ligand
-
(FLT3L). An important growth factor in dendritic cell (DC) development. Its receptor FLT3 is expressed on haematopoietic progenitor cells as well as on all DCs, and FLT3L administration causes uneven expansion of most DC subsets.
- Type 1 diabetes
-
(T1D; also known as insulin-dependent or juvenile diabetes). A disease that arises in children and young adults and that is caused by the destruction of pancreatic insulin-producing β-islet cells. It is thought that β-islet cell destruction is mediated by CD4+ and CD8+ T cells that are specific to β-islet cell autoantigens, such as insulin, zinc transporter 8 (ZNT8), islet-specific glucose-6-phospatase catalytic subunit-related protein (IGRP) and chromogranin A. Inbred non-obese diabetic (NOD) mice represent an excellent spontaneous model of T1D, a disease which is controlled by multiple genetic loci.
- Systemic lupus erythematosus
-
(SLE). A disease characterized by the production of autoantibodies against self-DNA, chromatin, and RNA-associated proteins. The resulting immune complexes are deposited and induce inflammation in multiple tissues, particularly in kidney glomeruli (glomerulonephritis). Mouse models of spontaneous SLE include: the NZB/NZW strain and its derivative strains; MRL–FasLpr mice with a mutation in the death receptor CD95; and models with overexpression of Toll-like receptor 7 (TLR7; for example, Yaa locus-containing strains and Tlr7-transgenic mice).
- Autoimmune myocarditis
-
A form of heart inflammation that is commonly associated with dilated cardiomyopathy, which is the most common cause of heart failure in young adults. It can be modelled in mice with experimental autoimmune myocarditis (EAM), which is induced by immunization with cardiac proteins such as the α-myosin heavy chain.
- Multiple sclerosis
-
A disease that is most frequent in young female adults as a relapsing-remitting disease. It involves inflammation and focal neurodegeneration of the white matter of the central nervous system, which results from an autoimmune response to the components of the myelin sheath.
- Experimental autoimmune encephalomyelitis
-
(EAE). A classical induced model of multiple sclerosis. EAE can be either actively induced by immunization against proteins of the myelin sheath, or passively induced by the adoptive transfer of encephalitogenic T helper cells. Transgenic models of EAE expressing myelin-specific T cell receptors are also widely studied.
- Psoriasis
-
A chronic inflammation of the skin that is characterized by vascular hyperplasia and keratinocyte hyperproliferation, and is accompanied by a local pro-inflammatory milieu and immune cell infiltration. Mouse models typically recapitulate only some aspects of the disease and include genetic manipulation or chemical activation of immune responses (for example, with the Toll-like receptor 7 agonist imiquimod).
Rights and permissions
About this article
Cite this article
Ganguly, D., Haak, S., Sisirak, V. et al. The role of dendritic cells in autoimmunity. Nat Rev Immunol 13, 566–577 (2013). https://doi.org/10.1038/nri3477
Published:
Issue Date:
DOI: https://doi.org/10.1038/nri3477
This article is cited by
-
Differentiation, maturation, and collection of THP-1-derived dendritic cells based on a PEG hydrogel culture platform
Biotechnology Letters (2024)
-
Signaling pathways involved in the biological functions of dendritic cells and their implications for disease treatment
Molecular Biomedicine (2023)
-
CTCF controls three-dimensional enhancer network underlying the inflammatory response of bone marrow-derived dendritic cells
Nature Communications (2023)
-
TREMble Before TREM2: The Mighty Microglial Receptor Conferring Neuroprotective Properties in TDP-43 Mediated Neurodegeneration
Neuroscience Bulletin (2023)
-
Advances in the modulation of ROS and transdermal administration for anti-psoriatic nanotherapies
Journal of Nanobiotechnology (2022)