Migratory CD103+ and lymphoid-resident CD8+ dendritic cells (DCs) share many attributes, such as dependence on the same transcription factors, cross-presenting ability and expression of certain surface molecules, such that it has been proposed they belong to a common sub-lineage. The functional diversity of the two DC types is nevertheless incompletely understood. Here we reveal that upon skin infection with herpes simplex virus, migratory CD103+ DCs from draining lymph nodes were more potent at inducing Th17 cytokine production by CD4+ T cells than CD8+ DCs. This superior capacity to drive Th17 responses was also evident in CD103+ DCs from uninfected mice. Their differential potency to induce Th17 differentiation was reflected by higher production of IL-1β and IL-6 by CD103+ DCs compared with CD8+ DCs upon stimulation. The two types of DCs from isolated lymph nodes also differ in expression of certain pattern recognition receptors. Furthermore, elevated levels of GM-CSF, typical of those found in inflammation, substantially increased the pool size of CD103+ DCs in lymph nodes and skin. We argue that varied levels of GM-CSF may explain the contrasting reports regarding the positive role of GM-CSF in regulating development of CD103+ DCs. Together, we find that these two developmentally closely-related DC subsets display functional differences and that GM-CSF has differential effect on the two types of DCs.
References
[1]
Aliberti J, Schulz O, Pennington DJ, Tsujimura H, Reis e Sousa C, et al. (2003) Essential role for ICSBP in the in vivo development of murine CD8alpha + dendritic cells. Blood 101: 305–310. doi: 10.1182/blood-2002-04-1088
[2]
Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, et al. (2008) Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science 322: 1097–1100. doi: 10.1126/science.1164206
[3]
Ginhoux F, Liu K, Helft J, Bogunovic M, Greter M, et al. (2009) The origin and development of nonlymphoid tissue CD103+ DCs. J Exp Med 206: 3115–3130. doi: 10.1084/jem.20091756
[4]
Jackson JT, Hu Y, Liu R, Masson F, D'Amico A, et al. (2011) Id2 expression delineates differential checkpoints in the genetic program of CD8alpha(+) and CD103(+) dendritic cell lineages. EMBO J 30: 2690–2704. doi: 10.1038/emboj.2011.163
[5]
Bachem A, Guttler S, Hartung E, Ebstein F, Schaefer M, 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. doi: 10.1084/jem.20100348
[6]
Crozat K, Tamoutounour S, Vu Manh TP, Fossum E, Luche H, et al. (2011) Cutting Edge: Expression of XCR1 Defines Mouse Lymphoid-Tissue Resident and Migratory Dendritic Cells of the CD8{alpha}+ Type. J Immunol 187: 4411–4415. doi: 10.4049/jimmunol.1101717
[7]
Poulin LF, Reyal Y, Uronen-Hansson H, Schraml BU, Sancho D, 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. doi: 10.1182/blood-2012-01-406967
[8]
McLellan AD, Kapp M, Eggert A, Linden C, Bommhardt U, et al. (2002) Anatomic location and T-cell stimulatory functions of mouse dendritic cell subsets defined by CD4 and CD8 expression. Blood 99: 2084–2093. doi: 10.1182/blood.v99.6.2084
[9]
Qiu CH, Miyake Y, Kaise H, Kitamura H, Ohara O, et al. (2009) Novel subset of CD8{alpha}+ dendritic cells localized in the marginal zone is responsible for tolerance to cell-associated antigens. J Immunol 182: 4127–4136. doi: 10.4049/jimmunol.0803364
[10]
Zhan Y, Carrington EM, van Nieuwenhuijze A, Bedoui S, Seah S, et al. (2011) GM-CSF increases cross-presentation and CD103 expression by mouse CD8 spleen dendritic cells. Eur J Immunol 41: 2585–2595. doi: 10.1002/eji.201141540
[11]
den Haan JM, Lehar SM, Bevan MJ (2000) CD8(+) but not CD8(？) dendritic cells cross-prime cytotoxic T cells in vivo. J Exp Med 192: 1685–1696. doi: 10.1084/jem.192.12.1685
[12]
Bedoui S, Whitney PG, Waithman J, Eidsmo L, Wakim L, et al. (2009) Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells. Nat Immunol 10: 488–495. doi: 10.1038/ni.1724
[13]
Reis e Sousa C, Hieny S, Scharton-Kersten T, Jankovic D, Charest H, et al. (1997) In vivo microbial stimulation induces rapid CD40 ligand-independent production of interleukin 12 by dendritic cells and their redistribution to T cell areas. J Exp Med 186: 1819–1829. doi: 10.1084/jem.186.11.1819
[14]
Maldonado-Lopez R, De Smedt T, Michel P, Godfroid J, Pajak B, et al. (1999) CD8alpha+ and CD8alpha- subclasses of dendritic cells direct the development of distinct T helper cells in vivo. J Exp Med 189: 587–592. doi: 10.1084/jem.189.3.587
[15]
Hochrein H, Shortman K, Vremec D, Scott B, Hertzog P, et al. (2001) Differential production of IL-12, IFN-alpha, and IFN-gamma by mouse dendritic cell subsets. J Immunol 166: 5448–5455. doi: 10.4049/jimmunol.166.9.5448
[16]
Mashayekhi M, Sandau MM, Dunay IR, Frickel EM, Khan A, et al. (2011) CD8alpha(+) Dendritic Cells Are the Critical Source of Interleukin-12 that Controls Acute Infection by Toxoplasma gondii Tachyzoites. Immunity 35: 249–259. doi: 10.1016/j.immuni.2011.08.008
[17]
Zhan Y, Xu Y, Seah S, Brady JL, Carrington EM, et al. (2010) Resident and Monocyte-Derived Dendritic Cells Become Dominant IL-12 Producers under Different Conditions and Signaling Pathways. J Immunol 185: 2125–2133. doi: 10.4049/jimmunol.0903793
[18]
King IL, Kroenke MA, Segal BM (2010) GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization. J Exp Med 207: 953–961. doi: 10.1084/jem.20091844
[19]
Edelson BT, Kc W, Juang R, Kohyama M, Benoit LA, et al. (2010) Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med 207: 823–836. doi: 10.1084/jem.20091627
[20]
Davey GM, Wojtasiak M, Proietto AI, Carbone FR, Heath WR, et al. (2010) Cutting edge: priming of CD8 T cell immunity to herpes simplex virus type 1 requires cognate TLR3 expression in vivo. J Immunol 184: 2243–2246. doi: 10.4049/jimmunol.0903013
[21]
Kupz A, Guarda G, Gebhardt T, Sander LE, Short KR, et al. (2012) NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8(+) T cells. Nat Immunol 13: 162–169. doi: 10.1038/ni.2195
[22]
Eisenbarth SC, Williams A, Colegio OR, Meng H, Strowig T, et al. (2012) NLRP10 is a NOD-like receptor essential to initiate adaptive immunity by dendritic cells. Nature 484: 510–513. doi: 10.1038/nature11012
[23]
Zhan Y, Xu Y, Lew AM (2012) The regulation of the development and function of dendritic cell subsets by GM-CSF: more than a hematopoietic growth factor. Mol Immunol 52: 30–37. doi: 10.1016/j.molimm.2012.04.009
[24]
Vremec D, Zorbas M, Scollay R, Saunders DJ, Ardavin CF, et al. (1992) The surface phenotype of dendritic cells purified from mouse thymus and spleen: investigation of the CD8 expression by a subpopulation of dendritic cells. J Exp Med 176: 47–58. doi: 10.1084/jem.176.1.47
[25]
Zhan Y, Vega-Ramos J, Carrington EM, Villadangos JA, Lew AM, et al. (2012) The inflammatory cytokine, GM-CSF, alters the developmental outcome of murine dendritic cells. Eur J Immunol 42: 2889–2900. doi: 10.1002/eji.201242477
[26]
Greter M, Helft J, Chow A, Hashimoto D, Mortha 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. doi: 10.1016/j.immuni.2012.03.027
[27]
Edelson BT, Bradstreet TR, Wumesh KC, Hildner K, Herzog JW, et al. (2011) Batf3-dependent CD11b(low/-) peripheral dendritic cells are GM-CSF-independent and are not required for Th cell priming after subcutaneous immunization. PLoS One 6: e25660. doi: 10.1371/journal.pone.0025660
[28]
Seymour JF, Lieschke GJ, Grail D, Quilici C, Hodgson G, et al. (1997) Mice lacking both granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF have impaired reproductive capacity, perturbed neonatal granulopoiesis, lung disease, amyloidosis, and reduced long-term survival. Blood 90: 3037–3049.
[29]
Lang RA, Metcalf D, Cuthbertson RA, Lyons I, Stanley E, et al. (1987) Transgenic mice expressing a hemopoietic growth factor gene (GM-CSF) develop accumulations of macrophages, blindness, and a fatal syndrome of tissue damage. Cell 51: 675–686. doi: 10.1016/0092-8674(87)90136-x
[30]
Barnden MJ, Allison J, Heath WR, Carbone FR (1998) Defective TCR expression in transgenic mice constructed using cDNA-based alpha- and beta-chain genes under the control of heterologous regulatory elements. Immunol Cell Biol 76: 34–40. doi: 10.1046/j.1440-1711.1998.00709.x
[31]
Hogquist KA, Jameson SC, Heath WR, Howard JL, Bevan MJ, et al. (1994) T cell receptor antagonist peptides induce positive selection. Cell 76: 17–27. doi: 10.1016/0092-8674(94)90169-4
[32]
Schon MP, Arya A, Murphy EA, Adams CM, Strauch UG, et al. (1999) Mucosal T lymphocyte numbers are selectively reduced in integrin alpha E (CD103)-deficient mice. J Immunol 162: 6641–6649.
[33]
Kissenpfennig A, Henri S, Dubois B, Laplace-Builhe C, Perrin P, 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. doi: 10.1016/j.immuni.2005.04.004
[34]
Lech M, Avila-Ferrufino A, Skuginna V, Susanti HE, Anders HJ (2010) Quantitative expression of RIG-like helicase, NOD-like receptor and inflammasome-related mRNAs in humans and mice. Int Immunol 22: 717–728. doi: 10.1093/intimm/dxq058
[35]
Henri S, Poulin LF, Tamoutounour S, Ardouin L, Guilliams M, et al. (2010) CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells. J Exp Med 207: 189–206. doi: 10.1084/jem.20091964
[36]
Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, et al. (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183: 787–791. doi: 10.4049/jimmunol.0901363
[37]
Pooley JL, Heath WR, Shortman K (2001) Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8？ dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J Immunol 166: 5327–5330. doi: 10.4049/jimmunol.166.9.5327
[38]
Lin ML, Zhan Y, Proietto AI, Prato S, Wu L, et al. (2008) Selective suicide of cross-presenting CD8+ dendritic cells by cytochrome c injection shows functional heterogeneity within this subset. Proc Natl Acad Sci U S A 105: 3029–3034. doi: 10.1073/pnas.0712394105
[39]
Sathe P, Pooley J, Vremec D, Mintern J, Jin JO, et al. (2011) The acquisition of antigen cross-presentation function by newly formed dendritic cells. J Immunol 186: 5184–5192. doi: 10.4049/jimmunol.1002683
[40]
Dresch C, Ackermann M, Vogt B, de Andrade Pereira B, Shortman K, et al. (2011) Thymic but not splenic CD8 DCs can efficiently cross-prime T cells in the absence of licensing factors. Eur J Immunol 41: 2544–2555. doi: 10.1002/eji.201041374
[41]
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8: 942–949. doi: 10.1038/ni1496
[42]
Ouyang W (2010) Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine Growth Factor Rev 21: 435–441. doi: 10.1016/j.cytogfr.2010.10.007
[43]
McGeachy MJ, Bak-Jensen KS, Chen Y, Tato CM, Blumenschein W, et al. (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8: 1390–1397. doi: 10.1038/ni1539
[44]
Reynolds JM, Angkasekwinai P, Dong C (2010) IL-17 family member cytokines: regulation and function in innate immunity. Cytokine Growth Factor Rev 21: 413–423. doi: 10.1016/j.cytogfr.2010.10.002
[45]
Gomez-Rodriguez J, Sahu N, Handon R, Davidson TS, Anderson SM, et al. (2009) Differential expression of interleukin-17A and -17F is coupled to T cell receptor signaling via inducible T cell kinase. Immunity 31: 587–597. doi: 10.1016/j.immuni.2009.07.009
[46]
Ishigame H, Kakuta S, Nagai T, Kadoki M, Nambu A, et al. (2009) Differential roles of interleukin-17A and -17F in host defense against mucoepithelial bacterial infection and allergic responses. Immunity 30: 108–119. doi: 10.1016/j.immuni.2008.11.009
[47]
Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8: 533–544. doi: 10.1038/nri2356
[48]
Stockinger B, Veldhoen M (2007) Differentiation and function of Th17 T cells. Curr Opin Immunol 19: 281–286. doi: 10.1016/j.coi.2007.04.005
[49]
Bettelli E, Korn T, Oukka M, Kuchroo VK (2008) Induction and effector functions of T(H)17 cells. Nature 453: 1051–1057. doi: 10.1038/nature07036
[50]
Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, et al. (2011) RORgammat drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol 12: 560–567. doi: 10.1038/ni.2027
[51]
El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, et al. (2011) The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol 12: 568–575. doi: 10.1038/ni.2031
[52]
Campbell IK, van Nieuwenhuijze A, Segura E, O'Donnell K, Coghill E, et al. (2011) Differentiation of Inflammatory Dendritic Cells Is Mediated by NF-{kappa}B1-Dependent GM-CSF Production in CD4 T Cells. J Immunol 186: 5468–5477. doi: 10.4049/jimmunol.1002923
[53]
Sonderegger I, Iezzi G, Maier R, Schmitz N, Kurrer M, et al. (2008) GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival. J Exp Med 205: 2281–2294. doi: 10.1084/jem.20071119
