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Endogenous and tumour-derived microRNAs regulate cross-presentation in dendritic cells and consequently cytotoxic T cell function

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Abstract

Dendritic cells (DCs) are potent antigen presenting cells (APCs). They are also specialized in the induction of cytotoxic T lymphocyte mediated responses against extracellular antigens, including tumour-specific antigens, by presenting peptide-Major Histocompatibility Complex (MHC) I complexes to naïve CD8+ T cells in lymphoid tissues, a process called cross-presentation. Emerging evidence suggests that the efficiency of cross-presentation can be influenced by a unique set of microRNAs (miRNAs). Some are differentially expressed in the course of morphological and functional development of DCs while tumorigenic miRNAs (onco-miRs) can be delivered to and inserted into DCs via exosomes. The latter reprogram the miRNA repertoire of DCs, transforming them from effective APCs to negative modulators of immunity, ultimately aiding cancers to evade host immunity. On the other hand, endogenous microRNAs can influence cross-presentation either positively or negatively. In this review, we discuss the possible mechanisms by which specific miRNAs influence cross-presentation as well as the viability of manipulating the expression of miRNAs that regulate DC cross-presentation as a potential cancer immunotherapy intervention.

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References

  • Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511

    Article  CAS  Google Scholar 

  • Bachem A et al (2010) Superior antigen cross-presentation and XCR1 expression define human CD11c+ CD141+ cells as homologues of mouse CD8+ dendritic cells. J Exp Med 207:1273–1281

    Article  CAS  Google Scholar 

  • Bai Y et al (2012) Integrin CD11b negatively regulates TLR9-triggered dendritic cell cross-priming by upregulating microRNA-146a. J Immunol 188:5293–5302

    Article  CAS  Google Scholar 

  • Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  CAS  Google Scholar 

  • Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    Article  CAS  Google Scholar 

  • Bellone G et al (2006) Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells. J Immunol 177:3448–3460

    Article  CAS  Google Scholar 

  • Bevan MJ (1976) Minor H antigens introduced on H-2 different stimulating cells cross-react at the cytotoxic T cell level during in vivo priming. J Immunol 117:2233–2238

    CAS  Google Scholar 

  • Blander JM, Sander LE (2012) Beyond pattern recognition: five immune checkpoints for scaling the microbial threat. Nat Rev Immunol 12:215–225

    Article  CAS  Google Scholar 

  • Bloomston M et al (2007) MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297:1901–1908

    Article  CAS  Google Scholar 

  • Blum JS et al (2013) Pathways of antigen processing. Annu Rev Immunol 31:443

    Article  CAS  Google Scholar 

  • Burgdorf S et al (2007) Distinct pathways of antigen uptake and intracellular routing in CD4 and CD8 T cell activation. Science 316:612–616

    Article  CAS  Google Scholar 

  • Burgdorf S, Kurts C (2008) Endocytosis mechanisms and the cell biology of antigen presentation. Curr Opin Immunol 20:89–95

    Article  CAS  Google Scholar 

  • Burgdorf S et al (2008) Spatial and mechanistic separation of cross-presentation and endogenous antigen presentation. Nat Immunol 9:558–566

    Article  CAS  Google Scholar 

  • Busch M, Zernecke A (2012) microRNAs in the regulation of dendritic cell functions in inflammation and atherosclerosis. J Mol Med 90:877–885

    Article  CAS  Google Scholar 

  • Caminschi I et al (2008) The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement. Blood 112:3264–3273

    Article  CAS  Google Scholar 

  • Cebrian I et al (2011) Sec22b regulates phagosomal maturation and antigen crosspresentation by dendritic cells. Cell 147:1355–1368

    Article  CAS  Google Scholar 

  • Chen T et al (2011) MicroRNA-146a regulates the maturation process and pro-inflammatory cytokine secretion by targeting CD40L in oxLDL-stimulated dendritic cells. FEBS Lett 585:567–573

    Article  CAS  Google Scholar 

  • Cifuentes D et al (2010) A novel miRNA processing pathway independent of Dicer requires Argonaute2 catalytic activity. Science 328:1694–1698

    Article  CAS  Google Scholar 

  • Claus V et al (1998) Lysosomal enzyme trafficking between phagosomes, endosomes, and lysosomes in J774 macrophages phages. Enrichment of cathepsin H in early endosomes. J Biol Chem 273:9842–9851

    Article  CAS  Google Scholar 

  • Clayton A et al (2007) Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res 67:7458–7466

    Article  CAS  Google Scholar 

  • Crozat K et al (2010) The XC chemokine receptor 1 is a conserved selective marker of mammalian cells homologous to mouse CD8α+ dendritic cells. J Exp Med 207:1283–1292

    Article  CAS  Google Scholar 

  • Cubillos-Ruiz JR et al (2009) Polyethylenimine-based siRNA nanocomplexes reprogram tumor-associated dendritic cells via TLR5 to elicit therapeutic antitumor immunity. J Clin Invest 119:2231

    CAS  Google Scholar 

  • Cubillos-Ruiz JR et al (2012) Reprogramming tumor-associated dendritic cells in vivo using miRNA mimetics triggers protective immunity against ovarian cancer. Cancer Res 72:1683–1693

    Article  CAS  Google Scholar 

  • Curtsinger JM et al (2003) Signal 3 determines tolerance versus full activation of naive CD8 T cells dissociating proliferation and development of effector function. J Exp Med 197:1141–1151

    Article  CAS  Google Scholar 

  • Datta SK et al (2003) A subset of toll-like receptor ligands induces cross-presentation by bone marrow-derived dendritic cells. J Immunol 170:4102–4110

    Article  CAS  Google Scholar 

  • Delamarre L et al (2005) Differential lysosomal proteolysis in antigen-presenting cells determines antigen fate. Science 307:1630–1634

    Article  CAS  Google Scholar 

  • Desch AN et al (2011) CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell–associated antigen. J Exp Med 208:1789–1797

    Article  CAS  Google Scholar 

  • Du J et al (2012) Aberrant elevated microRNA-146a in dendritic cells (DC) induced by human pancreatic cancer cell line BxPC-3-conditioned medium inhibits DC maturation and activation. Med Oncol 29:2814–2823

    Article  CAS  Google Scholar 

  • Dueck A et al (2014) A miR-155-dependent microRNA hierarchy in dendritic cell maturation and macrophage activation. FEBS Lett 588:632–640

    Article  CAS  Google Scholar 

  • Dunand-Sauthier I et al (2011) Silencing of c-Fos expression by microRNA-155 is critical for dendritic cell maturation and function. Blood 117:4490–4500

    Article  CAS  Google Scholar 

  • Dzionek A et al (2000) BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 165:6037–6046

    Article  CAS  Google Scholar 

  • e Sousa CR (2006) Dendritic cells in a mature age. Nat Rev Immunol 6:476–483

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Fordham JB et al (2015) Regulation of miR-24, miR-30b, and miR-142-3p during macrophage and dendritic cell differentiation potentiates innate immunity. J Leukoc Biol 98:195–207

    Article  CAS  Google Scholar 

  • Fukao T et al (2007) An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 129:617–631

    Article  CAS  Google Scholar 

  • Galibert L et al (2005) Nectin-like protein 2 defines a subset of T-cell zone dendritic cells and is a ligand for class-I-restricted T-cell-associated molecule. J Biol Chem 280:21955–21964

    Article  CAS  Google Scholar 

  • Garzon R et al (2010) Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov 9:775–789

    Article  CAS  Google Scholar 

  • Greither T et al (2010) Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival. Int J Cancer 126:73–80

    Article  CAS  Google Scholar 

  • Guler R et al (2011) PKCδ regulates IL-12p40/p70 production by macrophages and dendritic cells, driving a type 1 healer phenotype in cutaneous leishmaniasis. Eur J Immunol 41:706–715

    Article  CAS  Google Scholar 

  • Hashimi ST et al (2009) MicroRNA profiling identifies miR-34a and miR-21 and their target genes JAG1 and WNT1 in the coordinate regulation of dendritic cell differentiation. Blood 114:404–414

    Article  CAS  Google Scholar 

  • Hashimoto D et al (2011) Dendritic cell and macrophage heterogeneity in vivo. Immunity 35:323–335

    Article  CAS  Google Scholar 

  • Heath WR, Carbone FR (2001) Cross-presentation, dendritic cells, tolerance and immunity. Annu Rev Immunol 19:47–64

    Article  CAS  Google Scholar 

  • Heinz LX et al (2006) Differential involvement of PU. 1 and Id2 downstream of TGF-β1 during Langerhans-cell commitment. Blood 107:1445–1453

    Article  CAS  Google Scholar 

  • Huang B et al (2008) TLR signaling by tumor and immune cells: a double-edged sword. Oncogene 27:218–224

    Article  CAS  Google Scholar 

  • Huntzinger E, Izaurralde E (2011) Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat Rev Genet 12:99–110

    Article  CAS  Google Scholar 

  • Huysamen C et al (2008) CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes. J Biol Chem 283:16693–16701

    Article  CAS  Google Scholar 

  • Iero M et al (2008) Tumour-released exosomes and their implications in cancer immunity. Cell Death Differ 15:80–88

    Article  CAS  Google Scholar 

  • Jancic C et al (2007) Rab27a regulates phagosomal pH and NADPH oxidase recruitment to dendritic cell phagosomes. Nat Cell Biol 9:367–378

    Article  CAS  Google Scholar 

  • Janeway CA et al (2001) The major histocompatibility complex and its functions. In: Janeway CA (ed) Immunobiology: the immune system in health and disease. Garland Science, New York

  • Jelinek I et al (2011) TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection. J Immunol 186:2422–2429

    Article  CAS  Google Scholar 

  • Joffre OP et al (2012) Cross-presentation by dendritic cells. Nat Rev Immunol 12:557–569

    Article  CAS  Google Scholar 

  • Kaplan DH (2010) In vivo function of Langerhans cells and dermal dendritic cells. Trends Immunol 31:446–451

    Article  CAS  Google Scholar 

  • Keller AM et al (2009) Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting. Blood 113:5167–5175

    Article  CAS  Google Scholar 

  • Kim YK, Kim VN (2007) Processing of intronic microRNAs. EMBO J 26:775–783

    Article  CAS  Google Scholar 

  • Kissenpfennig A et al (2005) Dynamics and function of langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating langerhans cells. Immunity 22:643–654

    Article  CAS  Google Scholar 

  • Klechevsky E et al (2008) Functional specializations of human epidermal Langerhans cells and CD14+ dermal dendritic cells. Immunity 29:497–510

    Article  CAS  Google Scholar 

  • Kok KH et al (2007) Human TRBP and PACT directly interact with each other and associate with dicer to facilitate the production of small interfering RNA. J Biol Chem 282:17649–17657

    Article  CAS  Google Scholar 

  • Koscianska E et al (2011) The role of Dicer protein partners in the processing of microRNA precursors. PLoS ONE 6:e28548

    Article  CAS  Google Scholar 

  • Krol J et al (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610

    CAS  Google Scholar 

  • Kuipers H et al (2010) Dicer-dependent microRNAs control maturation, function, and maintenance of Langerhans cells in vivo. J Immunol 185:400–409

    Article  CAS  Google Scholar 

  • Marigo I et al (2010) Tumor-induced tolerance and immune suppression depend on the C/EBPβ transcription factor. Immunity 32:790–802

    Article  CAS  Google Scholar 

  • Maurer T et al (2002) CpG-DNA aided cross-presentation of soluble antigens by dendritic cells. Eur J Immunol 32:2356–2364

    Article  CAS  Google Scholar 

  • Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258

    Article  CAS  Google Scholar 

  • Merad M et al (2008) Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells. Nat Rev Immunol 8:935–947

    Article  CAS  Google Scholar 

  • Merad M et al (2013) The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 31:563–604

    Article  CAS  Google Scholar 

  • Mi QS et al (2012) Lack of microRNA miR-150 reduces the capacity of epidermal Langerhans cell cross-presentation. Exp Dermatol 21:876–877

    Article  CAS  Google Scholar 

  • Mi Q-S et al (2013) Deletion of microRNA miR-223 increases Langerhans cell cross-presentation. Int J Biochem Cell Biol 45:395–400

    Article  CAS  Google Scholar 

  • Mittelbrunn M et al (2011) Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun 2:282

    Article  CAS  Google Scholar 

  • Montecalvo A et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766

    Article  CAS  Google Scholar 

  • Mycko MP et al (2012) MicroRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination. Proc Natl Acad Sci USA 109:E1248–E1257

    Article  CAS  Google Scholar 

  • Nagao K et al (2009) Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions. Proc Natl Acad Sci USA 106:3312–3317

    Article  CAS  Google Scholar 

  • Naik SH et al (2007) Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo. Nat Immunol 8:1217–1226

    Article  CAS  Google Scholar 

  • Nair P et al (2011) Co-ordination of incoming and outgoing traffic in antigen-Presenting cells by pattern recognition receptors and T cells. Traffic 12:1669–1676

    Article  CAS  Google Scholar 

  • Nair-Gupta P, Blander JM (2013) An updated view of the intracellular mechanisms regulating cross-presentation. Front Immunol 4:401

    Article  CAS  Google Scholar 

  • Naqvi AR et al (2015) Mir-24, mir-30b, and mir-142-3p regulate phagocytosis in myeloid inflammatory cells. J Immunol 194:1916–1927

    Article  CAS  Google Scholar 

  • Nestle F et al (1993) Characterization of dermal dendritic cells obtained from normal human skin reveals phenotypic and functionally distinctive subsets. J Immunol 151:6535–6545

    CAS  Google Scholar 

  • Oh JZ et al (2011) TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway. Blood 118:3028–3038

    Article  CAS  Google Scholar 

  • Onai N et al (2007) Identification of clonogenic common Flt3+ M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow. Nat Immunol 8:1207–1216

    Article  CAS  Google Scholar 

  • Palucka K, Banchereau J (2012) Cancer immunotherapy via dendritic cells. Nat Rev Cancer 12:265–277

    Article  CAS  Google Scholar 

  • Platzer B et al (2014) Antigen cross-presentation of immune complexes. Front Immunol 5:140

    Article  CAS  Google Scholar 

  • Pyfferoen L et al (2014) Lung tumours reprogram pulmonary dendritic cell immunogenicity at the microRNA level. Int J Cancer 135:2868–2877

    Article  CAS  Google Scholar 

  • Reichel M et al (2011) Silencing the silencer: strategies to inhibit microRNA activity. Biotechnol Lett 33:1285–1292

    Article  CAS  Google Scholar 

  • Reizis B (2010) Regulation of plasmacytoid dendritic cell development. Curr Opin Immunol 22:206–211

    Article  CAS  Google Scholar 

  • Robson NC et al (2010) Presentation of tumour antigens by dendritic cells and challenges faced. Curr Opin Immunol 22:137–144

    Article  CAS  Google Scholar 

  • Rock KL et al (2002) Protein degradation and the generation of MHC class I-presented peptides. Adv Immunol 80:1–70

    Article  CAS  Google Scholar 

  • Rodriguez A et al (2007) Requirement of bic/microRNA-155 for normal immune function. Science 316:608–611

    Article  CAS  Google Scholar 

  • Romani N et al (2010) Langerhans cells and more: langerin-expressing dendritic cell subsets in the skin. Immunol Rev 234:120–141

    Article  CAS  Google Scholar 

  • Ruby JG et al (2007) Intronic microRNA precursors that bypass Drosha processing. Nature 448:83–86

    Article  CAS  Google Scholar 

  • Savina A et al (2006) NOX2 controls phagosomal pH to regulate antigen processing during crosspresentation by dendritic cells. Cell 126:205–218

    Article  CAS  Google Scholar 

  • Schaible UE et al (2003) Apoptosis facilitates antigen presentation to T lymphocytes through MHC-I and CD1 in tuberculosis. Nat Med 9:1039–1046

    Article  CAS  Google Scholar 

  • Segura E, Villadangos JA (2009) Antigen presentation by dendritic cells in vivo. Curr Opin Immunol 21:105–110

    Article  CAS  Google Scholar 

  • Shortman K, Heath WR (2010) The CD8+ dendritic cell subset. Immunol Rev 234:18–31

    Article  CAS  Google Scholar 

  • Siegal FP et al (1999) The nature of the principal type 1 interferon-producing cells in human blood. Science 284:1835–1837

    Article  CAS  Google Scholar 

  • Smyth LA et al (2015) MicroRNAs affect dendritic cell function and phenotype. Immunology 144:197–205

    Article  CAS  Google Scholar 

  • Steinman RM (2007) Dendritic cells: versatile controllers of the immune system. Nat Med 13:1155–1159

    Article  CAS  Google Scholar 

  • Stoitzner P et al (2006) Langerhans cells cross-present antigen derived from skin. Proc Natl Acad Sci USA 103:7783–7788

    Article  CAS  Google Scholar 

  • Stroynowska-Czerwinska A et al (2014) The panorama of miRNA-mediated mechanisms in mammalian cells. Cell Mol Life Sci 71:2253–2270

    Article  CAS  Google Scholar 

  • Su X et al (2013) miRNomes of haematopoietic stem cells and dendritic cells identify miR-30b as a regulator of Notch1. Nat Commun 4:2903

    Google Scholar 

  • Szafranska A et al (2007) MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 26:4442–4452

    Article  CAS  Google Scholar 

  • Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820

    Article  CAS  Google Scholar 

  • Turner ML et al (2011) MicroRNAs regulate dendritic cell differentiation and function. J Immunol 187:3911–3917

    Article  CAS  Google Scholar 

  • Ueno H et al (2007) Dendritic cell subsets in health and disease. Immunol Rev 219:118–142

    Article  CAS  Google Scholar 

  • Valladeau J, Saeland S (2005) Cutaneous dendritic cells. Semin Immunol 17:273–283

  • Villadangos JA et al (2007) Outside looking in: the inner workings of the crosspresentation pathway within dendritic cells. Trends Immunol 28:45–47

    Article  CAS  Google Scholar 

  • Wang T et al (2004) Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48–54

    Article  CAS  Google Scholar 

  • Xiao C, Rajewsky K (2009) MicroRNA control in the immune system: basic principles. Cell 136:26–36

    Article  CAS  Google Scholar 

  • Xu Y-P et al (2012) Aging affects epidermal Langerhans cell development and function and alters their miRNA gene expression profile. Aging (Albany NY) 4:742–754

    Article  CAS  Google Scholar 

  • Yang J-S et al (2010) Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesis. Proc Natl Acad Sci USA 107:15163–15168

    Article  CAS  Google Scholar 

  • Yewdell JW et al (1999) Mechanisms of exogenous antigen presentation by MHC class I molecules in vitro and in vivo: implications for generating CD8+ T cell responses to infectious agents, tumors, transplants, and vaccines. Adv Immunol 73:1–77

    Article  CAS  Google Scholar 

  • Zheng Q et al (2012) MicroRNA miR-150 is involved in Vα14 invariant NKT cell development and function. J Immunol 188:2118–2126

    Article  CAS  Google Scholar 

  • Zhou H et al (2010) miR-155 and its star-form partner miR-155* cooperatively regulate type I interferon production by human plasmacytoid dendritic cells. Blood 116:5885–5894

    Article  CAS  Google Scholar 

  • Zhou L et al (2011) MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. Cell Mol Immunol 8:380–387

    Article  CAS  Google Scholar 

  • Zhou M et al (2014) Pancreatic cancer derived exosomes regulate the expression of TLR4 in dendritic cells via miR-203. Cell Immunol 292:65–69

    Article  CAS  Google Scholar 

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Kikete, S., Chu, X., Wang, L. et al. Endogenous and tumour-derived microRNAs regulate cross-presentation in dendritic cells and consequently cytotoxic T cell function. Cytotechnology 68, 2223–2233 (2016). https://doi.org/10.1007/s10616-016-9975-0

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