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• W2894569103 abstract "Dendritic cells (DCs) are important inducers and regulators of T-cell responses. They are able to activate and modulate the differentiation of CD4+ and CD8+ T cells. In the skin, there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103, and CD11b. Previous studies have suggested that dermal CD11b−CD207+ conventional type 1 DCs are indispensable for the priming of a skin homing cytotoxic T-lymphocyte response. However, conventional type 1 DCs are also the only skin DC subset capable of cross-presenting exogenous antigens on major histocompatibility complex class I. Thus, it remained unclear whether for antigens that do not require cross-presentation, such as viruses that infect DCs, other DC subtypes in the skin can contribute to cytotoxic T-lymphocyte priming. To address this question, we used a transgenic mouse model that allows inducible expression and presentation of a model antigen on selected subsets of dermal DCs. We show that for antigens presented via the conventional major histocompatibility complex class I presentation pathway, CD207– dermal DCs are fully competent to prime a skin homing cytotoxic T-lymphocyte response that is capable of protection against a local virus challenge and gives rise to skin resident memory CD8+ T cells. Dendritic cells (DCs) are important inducers and regulators of T-cell responses. They are able to activate and modulate the differentiation of CD4+ and CD8+ T cells. In the skin, there are at least five phenotypically distinct DC subpopulations that can be distinguished by differential expression of the cell surface markers CD207, CD103, and CD11b. Previous studies have suggested that dermal CD11b−CD207+ conventional type 1 DCs are indispensable for the priming of a skin homing cytotoxic T-lymphocyte response. However, conventional type 1 DCs are also the only skin DC subset capable of cross-presenting exogenous antigens on major histocompatibility complex class I. Thus, it remained unclear whether for antigens that do not require cross-presentation, such as viruses that infect DCs, other DC subtypes in the skin can contribute to cytotoxic T-lymphocyte priming. To address this question, we used a transgenic mouse model that allows inducible expression and presentation of a model antigen on selected subsets of dermal DCs. We show that for antigens presented via the conventional major histocompatibility complex class I presentation pathway, CD207– dermal DCs are fully competent to prime a skin homing cytotoxic T-lymphocyte response that is capable of protection against a local virus challenge and gives rise to skin resident memory CD8+ T cells. Conventional dendritic cells (cDCs) are the critical antigen-presenting cells for the priming of naïve CD4+ and CD8+ T cells, thereby playing a central role in the control of adaptive immunity. Based on their ontogeny and surface marker expression, cDCs throughout the different organs have been subdivided into two lineages. Conventional type 1 dendritic cells (cDC1s), the development of which depends on the transcription factors IRF8 and BATF3 and that can be identified by surface expression of XCR1 and conventional type 2 dendritic cells (cDC2s) that express IRF4 and Zeb2 and show surface expression of CD172a (Guilliams et al., 2014Guilliams M. Ginhoux F. Jakubzick C. Naik S.H. Onai N. Schraml B.U. et al.Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny.Nat Rev Immunol. 2014; 14: 571-578Crossref PubMed Scopus (1161) Google Scholar, Guilliams et al., 2016Guilliams M. Dutertre C.A. Scott C.L. McGovern N. Sichien D. Chakarov S. et al.Unsupervised high-dimensional analysis aligns dendritic cells across tissues and species.Immunity. 2016; 45: 669-684Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar, Scott et al., 2016Scott C.L. Soen B. Martens L. Skrypek N. Saelens W. Taminau J. et al.The transcription factor Zeb2 regulates development of conventional and plasmacytoid DCs by repressing Id2.J Exp Med. 2016; 213: 897-911Crossref PubMed Scopus (88) Google Scholar). In the skin, cDC1 express Langerin (CD207) and are CD11b–, whereas cDC2 are CD207– and may be either CD11b+ or CD11b– (Guilliams et al., 2016Guilliams M. Dutertre C.A. Scott C.L. McGovern N. Sichien D. Chakarov S. et al.Unsupervised high-dimensional analysis aligns dendritic cells across tissues and species.Immunity. 2016; 45: 669-684Abstract Full Text Full Text PDF PubMed Scopus (519) Google Scholar, Henri et al., 2009Henri S. Poulin L.F. Tamoutounour S. Ardouin L. Guilliams M. de Bovis B. et al.CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells.J Exp Med. 2009; 207: 189-206Crossref PubMed Scopus (314) Google Scholar). Experiments using monoclonal antibodies to target antigens to either cDC1 or cDC2 have suggested that cDC1 are superior in presentation on major histocompatibility complex (MHC) class I molecules, whereas cDC2 are more efficient in presentation on MHC class II (Dudziak et al., 2007Dudziak D. Kamphorst A.O. Heidkamp G.F. Buchholz V.R. Trumpfheller C. Yamazaki S. et al.Differential antigen processing by dendritic cell subsets in vivo.Science. 2007; 315: 107-111Crossref PubMed Scopus (1076) Google Scholar). Experiments in mice lacking cDC1 due to their deficiency in BATF3 identified cross-presentation of exogenous antigens on MHC class I as a unique functional property of cDC1 (Hildner et al., 2008Hildner K. Edelson B.T. Purtha W.E. Diamond M. Matsushita H. Kohyama M. et al.Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.Science. 2008; 322: 1097-1100Crossref PubMed Scopus (1352) Google Scholar). This has been supported by the finding that CD207+ cDC1 in the skin are the subset of dermal DCs able to cross-present antigens expressed in keratinocytes or antigens derived from viral or bacterial skin infections to CD8+ T cells and are crucial for cytotoxic T-lymphocyte (CTL) priming against such antigens (Bedoui et al., 2009Bedoui S. Whitney P.G. Waithman J. Eidsmo L. Wakim L. Caminschi I. et al.Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells.Nat Immunol. 2009; 10: 488-495Crossref PubMed Scopus (539) Google Scholar, Brewig et al., 2009Brewig N. Kissenpfennig A. Malissen B. Veit A. Bickert T. Fleischer B. et al.Priming of CD8+ and CD4+ T cells in experimental leishmaniasis is initiated by different dendritic cell subtypes.J Immunol. 2009; 182: 774-783Crossref PubMed Scopus (80) Google Scholar, Henri et al., 2009Henri S. Poulin L.F. Tamoutounour S. Ardouin L. Guilliams M. de Bovis B. et al.CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells.J Exp Med. 2009; 207: 189-206Crossref PubMed Scopus (314) Google Scholar, Seneschal et al., 2014Seneschal J. Jiang X. Kupper T.S. Langerin+ dermal DC, but not Langerhans cells, are required for effective CD8-mediated immune responses after skin scarification with vaccinia virus.J Invest Dermatol. 2014; 134: 686-694Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Cross-presentation is a crucial mechanism to mount CTL responses against antigens that are not expressed by the DCs themselves, such as bacterial, fungal, parasitic, and tumor antigens, and antigens from viruses that do not infect DCs (Joffre et al., 2012Joffre O.P. Segura E. Savina A. Amigorena S. Cross-presentation by dendritic cells.Nat Rev Immunol. 2012; 12: 557-569Crossref PubMed Scopus (1019) Google Scholar). However, many viruses do infect DCs directly (Freigang et al., 2005Freigang S. Probst H.C. van den Broek M. DC infection promotes antiviral CTL priming: the 'Winkelried' strategy.Trends Immunol. 2005; 26: 13-18Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar), and while some of them impair DC function to evade immune control, others still allow for robust CTL priming by direct antigen presentation (Nopora et al., 2012Nopora K. Bernhard C.A. Ried C. Castello A.A. Murphy K.M. Marconi P. et al.MHC class I cross-presentation by dendritic cells counteracts viral immune evasion.Front Immunol. 2012; 3: 348Crossref PubMed Scopus (36) Google Scholar). For CTL responses to antigens derived from infections of the skin, it has not been established whether CD207+ dermal cDC1s have, beyond their ability to cross-present exogenous antigens, unique functional properties that might be necessary for the priming of skin homing CTL responses and for the instruction of skin resident memory CD8+ T cells (Mueller and Mackay, 2016Mueller S.N. Mackay L.K. Tissue-resident memory T cells: local specialists in immune defence.Nat Rev Immunol. 2016; 16: 79-89Crossref PubMed Scopus (595) Google Scholar). To address this, we aimed to create a situation where CD8+ T-cell priming and differentiation of skin homing CTL responses could be studied without the need for antigen cross-presentation. To achieve antigen presentation by DCs independent of cross-presentation, we employed the DC-specific expression of T-cell epitopes (DIETER) transgenic mouse model, that uses a tamoxifen-inducible Cre/LoxP system to inducibly express a viral CTL epitope selectively on DC (Probst et al., 2003Probst 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. 2003; 18: 713-720Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). To restrict antigen expression to DC in the skin, we applied 4-hydroxy-tamoxifen (4-OHT) topically to the skin. Topical 4-OHT treatment resulted in antigen expression in all subsets of skin DCs, but not in resident DCs in the draining lymph nodes or in DCs at distal sites. Combining this model with mouse models lacking dermal cDC1s, we show that dermal CD207– migratory DCs are fully competent to prime CD8+ T-cell responses in skin draining lymph nodes and to induce skin homing CTLs, which can differentiate into skin resident memory T cells. We set out to investigate the capacity of different subsets of skin DCs to prime CD8+ T cells and to instruct homing and differentiation of skin resident memory CD8+ T cells independent of the DCs ability to take up and cross-present exogenous antigens. To this end, we employed the DIETER transgenic mouse model, which allows DC-specific and tamoxifen-inducible expression of a model antigen, namely the H-2Db restricted CTL Epitope GP33-41 from lymphocytic choriomeningitis virus (LCMV). We sought to restrict antigen expression to DCs in the skin by applying the inducing agent, 4-OHT, topical onto the skin of DIETER transgenic mice. To identify the cells targeted by topical 4-OHT treatment, we bred the CD11cCreERT transgene, which determines cell specificity of antigen expression in the DIETER mice, to a reporter mouse that expresses RFP upon Cre activity (Rosa26RFP). CD11cCreERT × Rosa26RFP mice were treated either systemically with tamoxifen or topically on the ear skin with 4-OHT and expression of RFP was determined in DCs isolated from the cervical lymph node and the spleen. In cervical lymph node cells, expression of CD11c and MHC class II was used to distinguish DCs that had immigrated from the skin (CD11cint MHC-IIhigh) from lymph node resident DCs (CD11chigh MHC IIint) (Figure 1a). Systemic treatment with tamoxifen induced RFP expression in 5–11% of DCs in both migratory and resident lymph node DCs and in splenic DCs. In contrast, RFP expression after topical 4-OHT treatment was found exclusively in migratory DC in skin draining lymph nodes, of which around 2% were RFP positive (Figure 1a, 1b), demonstrating, that topically applied 4-OHT activates Cre in DCs in the skin but does not reach the draining lymph nodes or distal lymphoid sites in sufficient concentrations to induce Cre activity there. To ascertain that the selective Cre activation in skin DCs by topical 4-OHT treatment also leads to skin DC, selective expression of the transgene encoded antigen in DIETER mice, we isolated DCs from the cervical lymph nodes of DIETER mice that had been treated either topically on the ear with 4-OHT or systemically with tamoxifen, sorted them into migratory and resident DCs by flow cytometry and investigated their capacity to present the GP33-41 antigen to TCR transgenic P14 Nur77GFP CD8+ T cells. TCR triggering, as reported by expression of GFP from the Nur77GFP transgene (Moran et al., 2011Moran A.E. Holzapfel K.L. Xing Y. Cunningham N.R. Maltzman J.S. Punt J. et al.T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse.J Exp Med. 2011; 208: 1279-1289Crossref PubMed Scopus (681) Google Scholar), was mediated only by migratory DCs from mice treated topically with 4-OHT, whereas both migratory and resident DCs could present antigen to P14 T cells, when tamoxifen was applied systemically (Figure 1c). Also, topical 4-OHT treatment of DIETER mice did not lead to the activation of specific T cells in the draining lymph node, when DC migration to the draining lymph node was prevented by resection of the treated skin area (Supplementary Figure S1 online). Collectively, these experiments establish that topical treatment of DIETER mice with 4-OHT induces antigen expression selectively in DC in the skin. To define the subsets of skin DCs targeted by topical application of 4-OHT in CD11cCreERT mice, we analyzed DCs from skin and skin draining lymph nodes of CD11cCreERT × Rosa26RFP mice topically treated with 20 μg 4-OHT, by flow cytometry, distinguishing seven subsets of DCs and macrophages in the skin and four subsets of migratory DCs in the draining lymph nodes, based on the expression of CD11b, CD207, CD103, ly6C, CD64 and CCR2 (Supplementary Figure S2a, S2b online) (Henri et al., 2009Henri S. Poulin L.F. Tamoutounour S. Ardouin L. Guilliams M. de Bovis B. et al.CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells.J Exp Med. 2009; 207: 189-206Crossref PubMed Scopus (314) Google Scholar, Tamoutounour et al., 2013Tamoutounour S. Guilliams M. Montanana Sanchis F. Liu H. Terhorst D. Malosse C. et al.Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin.Immunity. 2013; 39: 925-938Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar). We could detect Cre activity in all subsets of cDCs in the dermis as well as in epidermal Langerhans cells (LCs) and in CCR2+ monocyte-derived DCs in the skin but not in CCR2−CD64high dermal macrophages (Figure 2a, 2b ) or in any other cell type isolated from the skin (Supplementary Figure S3 online). While the frequency of cells expressing RFP as reporter of Cre activation was between 2% and 8% in most DC subsets in the skin, we found a remarkably high frequency (40–46%) of RFP-expressing cells amongst both the CD103+ and the CD103− subset of CD207+ dermal DCs at day 3 after the start of topical 4-OHT treatment (Figure 2a, 2b). A kinetic analysis of RFP-expressing migratory DC subsets arriving in the lymph nodes suggested this may be at least partially due to the slower emigration of this subset from the skin compared to cDC2s (Figure 2c) (Tomura et al., 2014Tomura M. Hata A. Matsuoka S. Shand F.H. Nakanishi Y. Ikebuchi R. et al.Tracking and quantification of dendritic cell migration and antigen trafficking between the skin and lymph nodes.Sci Rep. 2014; 4: 6030Crossref PubMed Scopus (123) Google Scholar). Due to the higher number of CD11b+ dermal DCs in the draining lymph nodes, CD207+ and CD207– DCs contributed to a similar extent to the number of migratory DCs with reported Cre activity in the draining lymph node (Figure 2c). Painting of the 4-OHT–treated skin site with a skin irritant greatly enhanced the number of RFP+ DCs in the draining lymph node (Supplementary Figure S4 online). Taken together, this shows that topical treatment of DIETER mice with 4-OHT induces antigen expression exclusively in DCs in the skin, which subsequently migrate to the draining lymph nodes and that all subsets of dermal DCs are targeted by topical 4-OHT.Figure 2Topical treatment of the skin with 4-hydroxytamoxifen targets all subsets of dermal dendritic cells, but not macrophages. CD11c-CreERT+ Rosa26-RFP+ mice were treated with 4-hydroxytamoxifen or vehicle topically on the ears at 2 consecutive days. Three days later, subsets of mononuclear phagocytes isolated from the skin (a) or from skin-draining lymph nodes (b, c) were analyzed for RFP expression by flow cytometry. (c) Fraction of RFP+ dendritic cells of the indicated subsets among all migratory dendritic cells. One representative of five mice (a, b) or mean and standard deviation (c) is shown. dDC, dermal dendritic cell; LC, Langerhans cell; moDC, monocyte-derived dendritic cell; 4-OHT, 4-hydroxytamoxifenView Large Image Figure ViewerDownload Hi-res image Download (PPT) Having ascertained that topical application of 4-OHT on the skin of DIETER mice induces antigen expression selectively in DCs in the skin, we sought to investigate whether this is sufficient to prime a cytotoxic T-cell response. To provide the DC maturation stimulus required for CTL priming (Probst et al., 2003Probst 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. 2003; 18: 713-720Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar), mice were injected with an agonistic antibody to CD40. Of note, anti-CD40 treatment also induces a massive mobilization of LCs from the epidermis and a markedly enhanced emigration of all subsets of dermal DCs to the skin draining lymph nodes (Supplementary Figure S5 online). Treatment of DIETER mice twice with 20 μg 4-OHT with concomitant systemic injection of 50 μg anti-CD40, resulted in robust expansion of CTL specific for the transgenic LCMV GP33-41 peptide (Figure 3a). About 80% of CTL primed by skin DCs expressed E-selectin ligand and P-selectin ligand, which have been shown to be essential for homing of T cells to inflamed skin (Ley and Kansas, 2004Ley K. Kansas G.S. Selectins in T-cell recruitment to non-lymphoid tissues and sites of inflammation.Nat Rev Immunol. 2004; 4: 325-335Crossref PubMed Scopus (386) Google Scholar, Staite et al., 1996Staite N.D. Justen J.M. Sly L.M. Beaudet A.L. Bullard D.C. Inhibition of delayed-type contact hypersensitivity in mice deficient in both E-selectin and P-selectin.Blood. 1996; 88: 2973-2979Crossref PubMed Google Scholar). In contrast, when tamoxifen was applied systemically, resulting in antigen expression in DCs in all lymphoid and non-lymphoid organs, this induced a high frequency of tetramer positive CTL (Figure 3a), but only about 30% of primed LCMV GP33-41-specific CTL displayed the E-selectin ligand+ and P-selectin ligand+ skin homing phenotype (Figure 3b). CTL primed by skin DCs were highly effective in protecting the mice against a challenge infection at a distal site with a recombinant vaccinia virus expressing the LCMV GP33-41 antigen (Figure 3c). Experiments using cutaneous infection with vaccinia virus have suggested that CD207+ cDC1s are the subset of DCs responsible for priming of skin homing CD8+ T cells and differentiation of skin resident memory CD8+ T cells (TRM) (Iborra et al., 2016Iborra S. Martinez-Lopez M. Khouili S.C. Enamorado M. Cueto F.J. Conde-Garrosa R. et al.Optimal generation of tissue-resident but not circulating memory T cells during viral infection requires crosspriming by DNGR-1+ dendritic cells.Immunity. 2016; 45: 847-860Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Given the well-established superior capacity of this subset to cross-present exogenous antigens (Bedoui et al., 2009Bedoui S. Whitney P.G. Waithman J. Eidsmo L. Wakim L. Caminschi I. et al.Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells.Nat Immunol. 2009; 10: 488-495Crossref PubMed Scopus (539) Google Scholar), we wondered whether this would also apply to situations that do not require cross-presentation. To this end, we bred DIETER mice to mice lacking BATF3, which, on the C57BL/6 background, lack most cDC1s, including CD207+ DCs in the skin (Edelson et al., 2010Edelson B.T. KC W. Juang R. Kohyama M. Benoit L.A. Klekotka P.A. et al.Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells.J Exp Med. 2010; 207: 823-836Crossref PubMed Scopus (568) Google Scholar) and to mice that express the human diphtheria toxin receptor under control of the mouse CD207 promoter (Langerin diphtheria toxin receptor [DTR] mice), thus allowing for depletion of CD207+ cells by diphtheria toxin treatment. The absence of CD207+ DCs in the skin and draining lymph nodes of these mice was confirmed by flow cytometry (Supplementary Figure S6 online). DIETER × Batf3–/– and DIETER × CD207DTR mice were used to generate mixed bone marrow chimeras in which irradiated C57BL/6 mice were reconstituted with bone marrow from these mice mixed in a 1:1 ratio with wild-type C57BL/6 BM (Batf3–/– × DIETER+B6 → B6 and Langerin-DTR × DIETER + B6 → B6 chimeras). In the resulting chimeras, DIETER DCs capable of expressing the GP33-41 peptide are lacking from the CD207+ skin DC compartment, but all subtypes of DCs develop from the WT BM (Supplementary Figure S7 online). This takes away the homeostatic pressure for the compensatory development of cDC1 in Batf3–/– mice under inflammatory conditions that has been described (Tussiwand et al., 2012Tussiwand R. Lee W.L. Murphy T.L. Mashayekhi M. KC W. Albring J.C. et al.Compensatory dendritic cell development mediated by BATF-IRF interactions.Nature. 2012; 490: 502-507Crossref PubMed Scopus (298) Google Scholar). Induction of antigen presentation exclusively on CD207– DCs in the skin by topical 4-OHT treatment of Batf3–/– × DIETER + B6 → B6 or Langerin-DTR × DIETER + B6 → B6 chimeras that had been treated with diphtheria toxin elicited a robust CD8+ T-cell response of similar magnitude as the response in DIETER mice, where antigen was induced on all dermal DC subsets and in LCs or in DIETER→B6 BM chimeras, where antigen was induced on all subsets of dermal DC but not in LC (Figure 4a). Priming of a robust CD8+ T-cell response by dermal CD207– DCs was also observed both, when dermal DCs were activated by topical application of a ligand for Toll-like receptor 7 (Lopez et al., 2017Lopez P.A. Denny M. Hartmann A.K. Alflen A. Probst H.C. von Stebut E. et al.Transcutaneous immunization with a novel imiquimod nanoemulsion induces superior T cell responses and virus protection.J Dermatol Sci. 2017; 87: 252-259Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar) instead of systemic anti-CD40 application (Supplementary Figure S8 online). CD8+ T cells primed by CD207– skin DCs were predominantly of the P-selectin ligand+ E-selectin ligand+ skin homing phenotype and fully capable of protecting the mice from a challenge infection with a recombinant vaccinia virus expressing the LCMV GP33-41 peptide at a distant skin site (Figure 4b, 4c). To establish whether skin homing CD8+ T cells primed by CD207– DCs are able to differentiate to TRM cells, we primed P14 transgenic CD8+ T cells by inducing antigen expression either on all subtypes of skin DCs or exclusively on CD207– skin DCs by treating DIETER mice or Langerin-DTR × DIETER + B6 → B6 chimeras that had been depleted of CD207+ cells, with 4-OHT on the back skin, while inducing inflammation at a distal skin site (ear) by DNFB treatment. Forty days later, we detected substantial numbers of P14 transgenic CD8+ T cells co-expressing CD69 and CD103 in the DNFB treated ears (Figure 5a, 5b ). Numbers of CD69+CD103+ P14 transgenic TRM cells were comparable in the group where antigen had been induced on CD207– and on all subtypes of skin DCs, respectively, indicating that CD207– skin DCs are fully competent to induce priming of skin homing CD8+ T cells that establish skin resident memory. In this study, we use an inducible transgenic mouse model to evaluate the capacity of CD207– DCs in the skin to prime cytotoxic T-cell responses, to differentiate skin homing CTL, and to give rise to skin resident CD8+ memory T cells. Over the past several years, several genetical models have been developed that lack cDC1s either due to a deletion of one of the lineage-defining transcription factors BATF-3 or IRF-8 (Edelson et al., 2010Edelson B.T. KC W. Juang R. Kohyama M. Benoit L.A. Klekotka P.A. et al.Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells.J Exp Med. 2010; 207: 823-836Crossref PubMed Scopus (568) Google Scholar, Hildner et al., 2008Hildner K. Edelson B.T. Purtha W.E. Diamond M. Matsushita H. Kohyama M. et al.Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.Science. 2008; 322: 1097-1100Crossref PubMed Scopus (1352) Google Scholar, Schiavoni et al., 2002Schiavoni G. Mattei F. Sestili P. Borghi P. Venditti M. Morse 3rd, H.C. et al.ICSBP is essential for the development of mouse type I interferon-producing cells and for the generation and activation of CD8alpha(+) dendritic cells.J Exp Med. 2002; 196: 1415-1425Crossref PubMed Scopus (342) Google Scholar) or that allow depletion of cDC1s by diphtheria toxin due to their transgenic expression of the human DTR on cDC1s (Bennett et al., 2005Bennett C.L. van Rijn E. Jung S. Inaba K. Steinman R.M. Kapsenberg M.L. et al.Inducible ablation of mouse Langerhans cells diminishes but fails to abrogate contact hypersensitivity.J Cell Biol. 2005; 169: 569-576Crossref PubMed Scopus (365) Google Scholar, Kissenpfennig et al., 2005Kissenpfennig A. Henri S. Dubois B. Laplace-Builhe C. Perrin P. Romani N. et al.Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells.Immunity. 2005; 22: 643-654Abstract Full Text Full Text PDF PubMed Scopus (780) Google Scholar, Yamazaki et al., 2013Yamazaki C. Sugiyama M. Ohta T. Hemmi H. Hamada E. Sasaki I. et al.Critical roles of a dendritic cell subset expressing a chemokine receptor, XCR1.J Immunol. 2013; 190: 6071-6082Crossref PubMed Scopus (102) Google Scholar). These models allowed identifying cross-priming of CD8+ T-cell responses as a unique functional property of cDC1s (Hildner et al., 2008Hildner K. Edelson B.T. Purtha W.E. Diamond M. Matsushita H. Kohyama M. et al.Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity.Science. 2008; 322: 1097-1100Crossref PubMed Scopus (1352) Google Scholar). Studies that focused on immune responses in the skin confirmed the unique role of cDC1s, which in the skin are characterized by expression of the C-type lectin CD207, in the presentation of antigens expressed by keratinocytes (Henri et al., 2009Henri S. Poulin L.F. Tamoutounour S. Ardouin L. Guilliams M. de Bovis B. et al.CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells.J Exp Med. 2009; 207: 189-206Crossref PubMed Scopus (314) Google Scholar) and pathogens that do not infect DCs directly, such as Leishmania major (Brewig et al., 2009Brewig N. Kissenpfennig A. Malissen B. Veit A. Bickert T. Fleischer B. et al.Priming of CD8+ and CD4+ T cells in experimental leishmaniasis is initiated by different dendritic cell subtypes.J Immunol. 2009; 182: 774-783Crossref PubMed Scopus (80) Google Scholar). Surprisingly, a unique role of skin cDC1s was also found in cutaneous infections with HSV-1, vaccinia virus (Seneschal et al., 2014Seneschal J. Jiang X. Kupper T.S. Langerin+ dermal DC, but not Langerhans cells, are required for effective CD8-mediated immune responses after skin scarification with vaccinia virus.J Invest Dermatol. 2014; 134: 686-694Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar), and herpes (Bedoui et al., 2009Bedoui S. Whitney P.G. Waithman J. Eidsmo L. Wakim L. Caminschi I. et al.Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells.Nat Immunol. 2009; 10: 488-495Crossref PubMed Scopus (539) Google Scholar), although all three viruses do infect DCs (Bronte et al., 1997Bronte V. Carroll M.W. Goletz T.J. Wang M. Overwijk W.W. Marincola F. et al.Antigen expression by dendritic cells correlates with the therapeutic effectiveness of a model recombinant poxvirus tumor vaccine.Proc Natl Acad Sci USA. 1997; 94: 3183-3188Crossref PubMed Scopus (137) Google Scholar, Macleod et al., 2014Macleod B.L. Bedoui S. Hor J.L. Mueller S.N. Russell T.A. Hollett N.A. et al.Distinct APC subtypes drive spatially segregated CD4+ and CD8+ T-cell effector activity during skin infection with HSV-1.PLoS Pathog. 2014; 10: e1004303Crossref PubMed Scopus (23) Google Scholar). This raised the question of whether unique functional properties in addition to cross-presentation might confound the critical role of cDC1s in these virus infections. One of these properties might be the ability to migrate toward the chemokine XCL1 due to the expression the lineage-defining chemokine receptor XCR1, an interaction that has been suggested to be essential for efficient cytotoxic T-cell responses (Dorner et al., 2009Dorner B.G. Dorner M.B. Zhou X. Opitz C. Mora A. Guttler S. et al.Selective expression of the chemokine receptor XCR1 on cross-presenting dendritic" @default.
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• W2894569103 date "2019-02-01" @default.
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• W2894569103 title "Dermal CD207-Negative Migratory Dendritic Cells Are Fully Competent to Prime Protective, Skin Homing Cytotoxic T-Lymphocyte Responses" @default.
• W2894569103 cites W1659557739 @default.
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