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* Institute of Immunology, Hannover Medical School, Hannover, Germany; and
Institute of Molecular Immunology, National Research Center, Munich, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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, are specialized in presenting Ag exclusively to CD8+ T cells. In CCR7-deficient but not in plt/plt mice, Ag-carrying CD103+ DC are largely absent in the brLN, although CD103+ DC are present in the lung of CCR7-deficient mice. As a consequence, adoptively transferred CD8+ T cells can be activated under tolerizing conditions in plt/plt but not in CCR7-deficient mice. These data reveal that CD103+ brLN DC are specialized in cross-presenting innocuous inhaled Ag in vivo. Because these cells are largely absent in CCR7–/– mice, our findings strongly suggest that brLN CD103+ DC are lung-derived and that expression of CCR7 is required for their migration from the lung into its draining lymph node. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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+ dendritic cell (DC)3 subset has been identified for its capability to cross-present Ag to CD8+ T cells giving rise to two possible different outcomes: cross-priming or cross-tolerization (3, 4). Cross-tolerance implicates the induction of CD8+ T cell tolerance by cross-presentation of self-Ags; by contrast, cross-priming involves the activation of CD8+ T cells for the generation of CTL effector cells. It has been shown recently that the capacity of DC for cross-presenting Ags depends on their Ag-processing properties, suggesting that the CD8+ DC subset has specialized machinery for cross-presenting self-Ags that is probably absent or less effective in other DC subsets (5). In contrast to the situation described for self-Ags, little is known about DC that cross-present innocuous inhaled Ag for cross-tolerization.
A recent report has identified the CD103+ DC in mice as a major DC population residing in the lung mucosa (6). CD103 (E) is the -chain of the E
7 integrin, which has been reported to be essential for the adhesion of human and mice intestinal lymphocytes to epithelial cells through the interactions with E-cadherin (7). CD103+ DC in the lung do not express the typical plasmacytoid DC (B220, Gr-1) or lymphoid markers (CD8), but express high amounts of CD11c, MHC class II, and low levels of CD11b (6).
We have previously demonstrated that CCR7 expression plays a pivotal role for the mobilization of DC from the skin (8), the intestine (9), and the lung (10) to the respective draining lymph nodes (LN). This migration is indispensable for the immunological relevant transport of Ag to tolerize CD4+ T cells. Consequently, CCR7-deficient mice fail to induce tolerance toward ingested (9) or inhaled Ags (10).
Based on these observations, we hypothesized that the impaired migration of lung-derived DC may also influence cross-presentation of innocuous Ag and the subsequent Ag-driven CD8+ T cell proliferation. In agreement with this concept, we now demonstrate that the adoptive transfer of OVA-loaded CCR7-deficient bone marrow-derived DC (BMDC) to C57BL/6 (B6) recipients, which also received CFSE-labeled OT-I cells, failed to induce proliferation of the adoptively transferred OT-I cells. Of interest, OT-I proliferation could be rescued when B6 BMDC were transferred intratracheally (i.t.) to CCR7-deficient recipients. Further analysis of this process revealed that Ag-carrying CD11chighCD11blowCD8–CD103+ DC, present in the brLN of wild-type and plt/plt, but almost absent in CCR7-deficient mice, have evolved to acquire specialized functions for cross-priming innocuous Ag to CD8+ T cells under tolerogenic conditions. In contrast, CD11cintCD11bhighCD103– DC are specialized in presenting innocuous Ag to CD4+ T cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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CCR7-deficient mice (11) were backcrossed for eight generations to C57BL/6 mice. C57BL/6 Ly5.2 (CD45.2), plt/plt, OT-I Thy1.1, and OT-II Ly5.1 mice, which carry a transgenic TCR for the H2-Kb-restricted SIINFEKL peptide derived from OVA257–264 or for the H2-Ab-restricted ISQAVHAAHAEINEAGR peptide derived from OVA323–339, were also used in this study. All the mice strains were bred and maintained under specific pathogen-free conditions at the Central Animal Facility of Hannover Medical School (Hannover, Germany) or were purchased from Charles River Breeding Laboratories. All animal experiments were conducted in accordance with local and institutional guidelines.
Generation of OVA-loaded BMDC
BMDC of wild-type and CCR7-deficient mice were generated as previously described (8). Briefly, bone marrow cells were harvested from femurs and tibiae and subsequently cultured in complete medium supplemented with 30 ng/ml GM-CSF. At day 3, culture medium was removed and the cells were selected by adherence. Four days later, cells were incubated for 24 h with 100 µg/ml OVA grade VI (Sigma-Aldrich) and 1 µg/ml LPS (Sigma-Aldrich). At day 8, BMDC were washed extensively with PBS and i.t. injected.
Intratracheal instillation of OVA and Ag-pulsed DC in vitro
Mice were anesthetized i.p. with 0.2 mg of ketamine and 0.02 mg of xylazine per gram of body weight. A blunt cannula (0.7 x 19 mm, Introcan; B. Braun) was gently introduced through the larynx into the trachea under visual control (Head-worn Loupe KS; Zeiss). A volume of 60 µl of extensively washed OVA-loaded BMDC or Cy5-labeled OVA (1 mg/ml in PBS) was i.t. injected. All batches of OVA were tested for the presence of LPS (LAL QCL 1000; BioWhittaker-Cambrex), and only batches containing <5 EU/mg were used.
Isolation of brLN DC
The thoracic cavity was dissected and the brLNs were exposed, isolated, and minced. DC were released from the brLNs by enzymatic digestion using RPMI 1640 containing 25 µg/ml DNase I (Roche), 10% FCS, 25 mM HEPES, and 500 µg/ml collagenase D (Roche) for 30 min at 37°C on an orbital shaker at 200 rpm. The cell suspension obtained was filtered using a nylon mesh. Finally, the cells were washed twice with PBS containing 2% FCS and 2 mM EDTA.
Flow cytometry
The DC of brLNs were prepared following the protocol described. All the cell suspensions were preincubated with 2 µg/ml blocking anti-FcR (2.4G2) before staining to reduce nonspecific binding. The following mAbs were used: CD3 (17A2), CD4 (RMCD4-2), CD8 (RMCD8-2), CD8 (53-6.7), CD11b (M1/70.15), CD11c (HL3), CD205 (NLDC-145), and CD19 (1D3) were purified and labeled in our laboratory; CD2 (RM2-5), CD18 (C71/16), CD11a (I21/7), CD80 (16-10A1), CD86 (RMMP-1), CD49d (428), CD49e (5H10-27), PDL1 (MIH3), PDL2 (TY25), CD40 (3/23), rat isotype control (R35-95), MHC class II (IAb) (AF6-120.1), Ly6c (AL-21), V2 (B20.1), V5 (MR9-4), and CD103 (M290) were purchased from BD Biosciences; 33D1 was obtained from eBioscience. Before i.t. transfer, BMDC differentiation was monitored applying mAbs to CD11c, IAb, and CD86. The brLN cell suspensions were stained with anti CD3, CD19, CD11c, and CD103 mAbs. Consequently, CD11c+CD103+OVA-Cy5+CD3–CD19– as well as CD11c+CD103–OVA-Cy5+CD3–CD19– DC were sorted on a FACSAria cell sorter (BD Biosciences). The purity of sorted DC was always >96%. Dead cells and debris were excluded by propidium iodide or DAPI (4',6'-diamido-2-phenylindole hydrochloride) staining. Flow cytometry acquisition was conducted on a LSR-II cytometer (BD Biosciences) while data analysis was performed using WinList 5.0 (Verity Software House).
Adoptive transfer of OVA-specific T cells from TCR transgenic mice
Spleen and peripheral LN of OT-I Thy1.1 or OT-II Ly5.1 mice were minced through a nylon mesh. Cells were washed twice with PBS and adjusted according to the number of V2+V5+ cells. A total of 5 x 107cells/ml were labeled with 5 µM CFSE (Molecular Probes) in PBS at 37°C for 10 min. The reaction was stopped by adding 2 volumes of cold RPMI 1640 containing 10% FCS followed by two washes in PBS. Each recipient received i.v. 15 x 106 OT-I T cells into the tail vein.
Aerosol treatment
In some experiments, mice were treated in an aerosol chamber with OVA aerosol (1% in water) or water alone. At 24 h after of adoptive transfer of CFSE-labeled cells, OVA solution or water was vaporized for 20 min using a PariBoy vaporizer as previously described (10). On day 4, mice were sacrificed and the brLN as well a nondraining LN were analyzed by flow cytometry to monitor the rate of T cell division.
In vitro T cell proliferation
Mice i.v. received 60 µg of OVA-Cy5 in PBS in a total volume of 60 µl. The brLN were removed 24 h later and CD3–CD19–CD11c+OVA-Cy5+CD103+ DC or CD3–CD19–CD11c+OVA-Cy5+CD103– DC were isolated by flow sorting. DC (2000 cells) were seeded in U-bottom 96-well plate and cocultured with 15 x 104 OT-I or OT-II T cells. Proliferation of OT-I and OT-II T cells in triplicate wells was measured after 3 days by pulsing the cells with 1 µCi/well [methyl-3H]thymidine followed by further incubation for 16 h. Plates were harvested, and thymidine uptake was quantified in a beta counter (Microbeta TriLux; PerkinElmer).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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CD103 is expressed on 30–50% of the lung-derived CD11c+ DC migrating to the brLN (10). Thus, similar to the situation described for DC of the mesenteric LN (12) and lung (6), CD103+ and CD103– DC are present in the brLN of wild-type mice following i.t. instillation of 60 µg of Cy5-labeled OVA (Fig. 1A). Of interest, CD11c was expressed differentially on these DC, being more abundantly present in the CD103+ DC (Fig. 1A). Assessing the capacity for Ag uptake and presentation, CD103+ and CD103– DC were analyzed for the presence of OVA-Cy5+. OVA-Cy5 was found to be trapped with roughly equal efficiency by both CD103+ and CD103– DC (Fig. 1B).
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(Fig. 2B), indicating that neither CD103+ nor CD103– DC belong to the CD8+ DC or plasmacytoid DC subset. CD11c+ DC isolated from spleen were used as positive controls because they contain subpopulations positive for CD8 or the 33D1 Ag (Fig. 2B). Of interest, DC isolated from the brLN were negative for CD8 as well as 33D1 (Fig. 2B), but CD103+ and CD103– DC expressed CD205 to some degree (Fig. 2C).
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Besides the presentation of pathogen-derived Ags, airway DC are also capable of presenting inhaled innocuous Ags to T cells to induce tolerance. We therefore aimed to determine whether different airway DC subsets have evolved to become specialized in presenting harmless Ag to distinct T cell subsets. To that end, OVA-Cy5 was i.t. instilled in wild-type mice. After 24 h, CD11c+OVA-Cy5+CD103+ and CD11c+OVA-Cy5+CD103– DC were isolated by flow sorting from the brLN and cocultured in vitro with OT-I or OT-II T cells for 72 h before T cell proliferation was assessed by [3H]thymidine incorporation. Strikingly, CD103+ and CD103– DC displayed distinct capabilities in priming CD4+ or CD8+ T cells. Thus, OVA-Cy5+CD103+ DC efficiently cross-presented the OVA Ag to CD8+ T cells, whereas OVA-Cy5+CD103– DC almost lacked such stimulatory activity (Fig. 3A). Conversely, CD103– DC induced massive proliferation of CD4+ OT-II, but not CD8+ OT-I T cells (Fig. 3B). Although both CD103+ and CD103– DC exhibited similar competency in taking up innocuous Ag (Fig. 1B), these DC process and present Ag differently to CD4+ and CD8+ T cells.
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Because OVA-Cy5+CD103+ DC in wild-type animals are specialized in cross-presenting innocuous Ag, we were interested in assessing the presence of this cell population in the brLN of CCR7-deficient and plt/plt mice. The latter mouse strain represents a naturally occurring mutant that lacks expression of CCR7 ligands in LN but not in nonlymphoid organs such as the lung. We determined the percentage of CD11c+OVA-Cy5+CD103+ DC in collagenase-digested brLN of wild-type, CCR7-deficient, as well as plt/plt mice 24 h after i.t. instillation of OVA-Cy5. As depicted in Fig. 4A, we failed to observe any significant differences between wild-type and plt/plt mice regarding the frequency of OVA-loaded CD103+ DC. In contrast, the frequency of this cell population was severely reduced in CCR7–/– mice. Together with data published earlier (10), this observation suggests that the migration of CD103+ DC from the lung to the brLN depends on CCR7 expression on lung-residing DC. Because plt/plt mice still express the CCL21-leu gene in lymphatic endothelial cells of the lung, it seems likely that CCL21-Leu allows for the migration of CD103+ DC from the lung to its draining LN in this mouse strain.
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CCR7–/– mice are deficient whereas plt/plt mice are proficient in cross-presenting innocuous inhaled Ag in vivo
We subsequently compared the in vivo capacity of DC to cross-present inhaled Ag. To that end, wild-type, plt/plt, and CCR7-deficient mice were i.v. injected with CFSE-labeled OT-I T cells and 1 day later received an OVA aerosol. After an additional 4 days, the lung-draining LN was removed and analyzed. In wild-type and plt/plt mice, OVA-aerosol treatment induced Ag-specific proliferation of OT-I T cells, whereas Ag-induced proliferation was not detectable at all in CCR7-deficient mice (Fig. 5). Together with the previously reported data (10), these results strongly suggest that the lack of CCR7 prevents the migration of DC from the lung to the draining brLN and, because of that, CCR7-deficient mice fail to present and cross-present Ag within the brLN to OT-II and OT-I T cells, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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The lung of wild-type and CCR7-deficient mice contain CD103+ DC that are reduced in the brLN of CCR7-deficient mice compared with wild-type mice (6, 10). CCR7-deficient mice also show a reduced number of these DC in skin-draining LN (data not shown) and in the mesenteric LN (12), suggesting that, in general, immature DC residing between epithelia might require CCR7 expression for proper mobilization from the periphery to the draining LN. In contrast to CCR7-deficient mice, the percentage of Ag-carrying CD103+ DC is not significantly reduced in the brLN of plt/plt mice. Although this mutant lacks expression of CCR7 ligands in lymphoid organs, one isoform of CCL21 (CCL21-Leu) is still present in these mice in nonlymphoid organs such as the lung, particularly in the endothelium of the afferent lymphatics (20). Therefore, it seems conceivable that expression of CCL21-Leu on afferent lymphatic vessels in the lung of plt/plt mice is sufficient to allow for steady state migration of DC to the brLN in these mice.
Based on the differential expression of CD103, this study demonstrates the existence of two distinct DC subsets that have evolved different capabilities in priming CD8+ or CD4+ T cells in the brLN under tolerogenic conditions. In addition to CD103, these two DC subsets also express different levels of -integrins such as CD11a, CD11b, and CD11c. However, these subsets were indistinguishable regarding the expression of costimulatory molecules or any of the other markers tested in this study. Despite the fact that CD103+ and CD103– DC express similar amounts of costimulatory molecules, their interaction with T cells leads to largely opposing outcomes. CD103+ DC primarily cross-present Ag to CD8+ T cells, whereas CD103– DC prime CD4+ T cells in both wild-type and plt/plt mice, but not in CCR7-deficient animals. The distinct capabilities of the CD103 DC subsets to prime T cells seems not to be related to their ability to take up Ag because both DC subsets capture comparable amounts of OVA following i.t. instillation. Along this line, it has been recently shown that spleen-derived CD8+ and CD8– DC engulfed similar amounts of Ag, yet within the spleen, only the CD8+ DC subset is able to cross-present Ag to CD8+ T cells, whereas the CD8– DC more efficiently stimulates CD4+ T cell proliferation (5, 21). Furthermore, during the submission process of this report Dudziak et al. (22) reported that, within the spleen, only CD205+ DC are able to cross-present Ag, whereas another DC population, negative for CD8 but positive for the 33D1 Ag, is specialized for presentation on MHC class II. Of interest, this study could show that the ability to present or cross-present Ag is intrinsic to the DC subsets and this role is associated with increased expression of components of the MHC class II and MHC class I processing pathways, respectively. Remarkably, the CD8+ DC subset is largely absent in nonlymphoid tissues, such as skin (23), pancreas (24), stomach (25), and lung (26), and its contribution to the pool of migrating DC from the lung to the brLN seems to be of negligible relevance (10, 26, 27). Data provided in this study support this idea because CD103+ DC that cross-present Ag in the brLN lack CD8 expression. Along this line, the present study reveals that none of markers successfully used to discriminate presenting (33D1+) from cross-presenting (CD8+, CD205+) DC in the spleen can be used in the lung-draining brLN. Steady-state DC isolated from this lymphoid organ lack expression of CD8 as well as 33D1, and both the CD103+ as well as the CD103– DC weakly express CD205.
It is noteworthy to mention that several reports have recently suggested that CD103+ and CD103– DC isolated from the lung or the intestine might exhibit similar competence in stimulating OVA-specific CD4+ and CD8+ T cells (6, 12, 28). However, those studies were performed pulsing CD103+ and CD103– DC in vitro with OVA peptides. Applying this procedure, peptides are directly loaded to the MHC molecules from outside, circumventing the need for Ag uptake, processing, and presentation. In contrast, in the present study DC were loaded in vivo by i.t. application of the entire OVA protein. Together, these data suggest that both CD103+ and CD103– DC can present Ag to CD4+ as well as CD8+ T cells as long as the appropriate peptides gain access to the MHC groove. Because CD103+ and CD103– brLN DC serve opposing functions with regard to presentation and cross-presentation of exogenous Ag once loaded in vivo, it seems likely that both cell types may exhibit profound differences regarding Ag processing as recently described for CD205+ and 33D1+ DC of the spleen (22). In summary, our data reveal that Ag-carrying CD103+ brLN DC are specialized in cross-presenting innocuous inhaled Ag. Because these cells are largely absent in CCR7-deficient but not plt/plt mice, our data strongly suggest that brLN CD103+ DC are lung derived and that expression of CCR7 is required for their migration from the lung into its draining LN.
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Acknowledgments |
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Disclosures |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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Footnotes |
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1 This work was supported by a Grant SFB587-B3 from the German Research Foundation (to R.F.). 
2 Address correspondence and reprint requests to Dr. Reinhold Förster, Institute of Immunology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail address: foerster.reinhold{at}mh-hannover.de
3 Abbreviations used in this paper: DC, dendritic cell; BMDC, bone marrow-derived DC; LN, lymph node; brLN, bronchial LN; i.t., intratracheal(ly).
Received for publication January 9, 2007. Accepted for publication March 20, 2007.
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References |
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E)-7 integrin-positive epithelial dendritic cell population expressing Langerin and tight junction proteins. J. Immunol. 176: 2161-2172. E7 integrin. Nature 372: 190-193. [Medline]+ dendritic cells but not by Langerhans cells. Science 301: 1925-1928. cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J. Exp. Med. 198: 1527-1537. This article has been cited by other articles:
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  L. Fahlen-Yrlid, T. Gustafsson, J. Westlund, A. Holmberg, A. Strombeck, M. Blomquist, G. G. MacPherson, J. Holmgren, and U. Yrlid CD11chigh Dendritic Cells Are Essential for Activation of CD4+ T Cells and Generation of Specific Antibodies following Mucosal Immunization J. Immunol., October 15, 2009; 183(8): 5032 - 5041. [Abstract] [Full Text] [PDF]
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P. J. Dunne, B. Moran, R. C. Cummins, and K. H. G. Mills CD11c+CD8{alpha}+ Dendritic Cells Promote Protective Immunity to Respiratory Infection with Bordetella pertussis J. Immunol., July 1, 2009; 183(1): 400 - 410. [Abstract] [Full Text] [PDF]
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C.-H. Qiu, Y. Miyake, H. Kaise, H. Kitamura, O. Ohara, and M. Tanaka Novel Subset of CD8{alpha}+ Dendritic Cells Localized in the Marginal Zone Is Responsible for Tolerance to Cell-Associated Antigens J. Immunol., April 1, 2009; 182(7): 4127 - 4136. [Abstract] [Full Text] [PDF]
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A. Guerrero-Plata, D. Kolli, C. Hong, A. Casola, and R. P. Garofalo Subversion of Pulmonary Dendritic Cell Function by Paramyxovirus Infections J. Immunol., March 1, 2009; 182(5): 3072 - 3083. [Abstract] [Full Text] [PDF]
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N. Brewig, A. Kissenpfennig, B. Malissen, A. Veit, T. Bickert, B. Fleischer, S. Mostbock, and U. Ritter Priming of CD8+ and CD4+ T Cells in Experimental Leishmaniasis Is Initiated by Different Dendritic Cell Subtypes J. Immunol., January 15, 2009; 182(2): 774 - 783. [Abstract] [Full Text] [PDF]
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M.-L. del Rio, J.-I. Rodriguez-Barbosa, J. Bolter, M. Ballmaier, O. Dittrich-Breiholz, M. Kracht, S. Jung, and R. Forster CX3CR1+c-kit+ Bone Marrow Cells Give Rise to CD103+ and CD103- Dendritic Cells with Distinct Functional Properties J. Immunol., November 1, 2008; 181(9): 6178 - 6188. [Abstract] [Full Text] [PDF]
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E. Jaensson, H. Uronen-Hansson, O. Pabst, B. Eksteen, J. Tian, J. L. Coombes, P.-L. Berg, T. Davidsson, F. Powrie, B. Johansson-Lindbom, et al. Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans J. Exp. Med., September 1, 2008; 205(9): 2139 - 2149. [Abstract] [Full Text] [PDF]
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C. H. GeurtsvanKessel, M. A.M. Willart, L. S. van Rijt, F. Muskens, M. Kool, C. Baas, K. Thielemans, C. Bennett, B. E. Clausen, H. C. Hoogsteden, et al. Clearance of influenza virus from the lung depends on migratory langerin+CD11b- but not plasmacytoid dendritic cells J. Exp. Med., July 7, 2008; 205(7): 1621 - 1634. [Abstract] [Full Text] [PDF]
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) and CD11c+OVA-Cy5+CD103– (
) DC were flow-sorted from the brLN of wild-type animals following 24 h after i.t. instillation of Cy5-labeled OVA. CD103+ or CD103– DC (2000/well) were cocultured with 15 x 104 OT-I (A) or OT-II (B) T cells in triplicate as indicated. Three days later, cultures were pulsed with 1 µCi/well [3H]thymidine for 16 h before thymidine uptake was quantified. Data are mean ± SD for n = 3 independent experiments.
) mice was analyzed 24 h after i.t. instillation of OVA-Cy5 (mean ± SD). n.s., Not significant. *, p < 0.05. CD11c+OVA-Cy5+CD103+ and CD11c+OVA-Cy5+CD103– DC were flow-sorted from the brLN of wild-type and plt/plt mice 24 h after i.t. instillation of OVA-Cy5. As indicated, CD103+ or CD103– DC (2000 per well) were cocultured in triplicates with 15 x 104 OT-I (B) or OT-II (C) T cells for 3 days before they were pulsed with [3H]thymidine for 16 h. Proliferation was analyzed applying a beta counter. Data are mean ± SD with results from one experiment. Similar results were obtained in a second experiment.
