Distinct antigen trafficking from skin in the steady and active states
Miya Yoshino1,2,
Hidetoshi Yamazaki1,
Hideki Nakano3,
Terutaka Kakiuchi3,
Kazuo Ryoke2,
Takahiro Kunisada4 and
Shin-Ichi Hayashi1
1 Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, and 2 Division of Oral and Maxillofacial Biopathological Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan 3 Department of Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan 4 Department of Tissue and Organ Development, Regeneration and Advanced Medical Science, Gifu University Graduate School of Medicine, Gifu 500-8705, Japan
Correspondence to: M. Yoshino, Division of Immunology, Department of Molecular and Cellular Biology, School of Life Science, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan. E-mail: myoshi{at}grape.med.tottori-u.ac.jp
Transmitting editor: T. Hamaoka
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Abstract
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In antigen trafficking from the skin, it has been postulated that Langerhans cells/dendritic cells are activated after capturing exogenous antigens, up-regulate the expression of the chemokine receptor, CCR7, and migrate into lymphoid organs in response to the signaling of a chemokine, CCL21, which is expressed in lymphatic vessels and T cell zone stromal cells. Here we demonstrate that there is a distinct pathway of antigen trafficking from skin in the steady state that is independent of CCL21CCR7 signaling. Employing melanin granules as an endogenous traceable antigen, we developed a system for visualizing antigen trafficking using mice with melanocytosis in the skin. We found the abrogation of antigen trafficking into regional lymph nodes (LN) in CCL21-Ser-deficient paucity of lymph node T cells (plt) mice in the active state induced by lipopolysaccharide injection, corresponding with previous reports, but normal accumulation of antigen in regional LN under steady-state conditions. These findings suggest that self-antigen is trafficking constitutively using pathway(s) other than that of the active state and the constitutive trafficking might regulate self-reactivity of the immune system.
Keywords: dendritic cell, Langerhans cell, lymph node, paucity of lymph node T cell (plt), skin
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Introduction
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Dendritic cells (DC) play a role as sentinels of the immune surveillance system (1). Invasion of pathogenic microbes into the skin triggers the activation of Langerhans cells (LC) (one type of DC lineage cells in the epidermis), which then capture antigens, migrate to the regional lymph nodes (LN) and present them to immunocompetent cells (2,3). The activated LC express elevated levels of a chemokine receptor, CCR7, and migrate to the T cell area of skin regional LN where the ligands of CCR7, CCL19 (ELC)/CCL21 (SLC), are expressed (48). CCL19/CCL21-Ser-deficient paucity of lymph node T cells (plt) mice were found to fail to accumulate DC as well as naive T cells in the T cell area of peripheral LN, Peyers patches and spleen (9,10).
Although skin allografts, s.c. injection of stimulants and painting of contact sensitizers (such as FITC and TNBS) are popular methods for analyzing LC migration from the skin (35,1113), these treatments cause skin irritation, suggesting that any LC migration or function observed with these methods was occurring in the active state.
In our previous study, employing melanin granules (MG) as a traceable antigen, we developed a system for examining antigen trafficking from the skin to regional LN using two transgenic (Tg) mouse lines displaying melanocytosis in the skin (1416 ). We found the continual accumulation of MG from the skin to regional LN in the Tg mice without any stimulation, indicating that antigens were constitutively trafficked even in the steady state. We also demonstrated that the MG trafficking from the epidermis and even from the dermis was lacking in transforming growth factor (TGF)-ß1-null mice. The mice lack LC in the epidermis, but macrophages and Thy-1.2+ dendritic epidermal cells (Thy-1+ DEC) were normally present. Taken together, we have proposed that antigens from the epidermis and dermis in the steady state might be trafficked by TGF-ß1-dependent LC and their relatives, and that MG in the macrophages in the regional LN were carried by these DC lineage cells (16).
In this study, to assess the mechanism of LC/DC migration from the skin both in the steady and active states in vivo, the accumulation of MG-laden LC/DC was examined by using double-mutant plt/plt mice expressing the mast cell growth factor transgene (Mgf-Tg) in the keratinocytes, resulting in melanocytosis in the epidermis (14,16). In the active state, the numbers of DC bearing MG were not increased in plt/plt-Mgf-Tg mice, whereas the numbers were increased in heterozygous littermates in response to stimulus by i.v. lipopolysaccharide (LPS) injection. On the other hand, in the steady state, almost the same number of DC bearing MG accumulated in skin regional LN in both plt/plt-Mgf-Tg mice and their heterozygous littermate Mgf-Tg mice. These findings suggest that only the active-state pathway of LC trafficking from the skin to regional LN depends on CCR7CCL21 signaling, while there is a distinct pathway in the steady state that does not depend on signaling via CCR7.
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Methods
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Mice
BALB/c mice were purchased from Japan CLEA (Tokyo, Japan). C57BL/6-+/Mgf-Tg (Mgf-Tg) mice carrying full-length murine Mgf cDNA driven by the human cytokeratin 14 promoter (14) were crossed with BALB/c-plt/plt (plt/plt) mice and the F1 mice carrying the transgene were backcrossed with plt/plt to produce plt/plt-Mgf-Tg mice. The mice were maintained in the Animal Research Center, Faculty of Medicine, Tottori University. plt/plt homozygotes were screened by PCR analysis of genomic DNA prepared from tails using the following primers: mouse STS markers D4Mit237 and D4Mit286 (sequence data are available from GenBank/EMBL/DDBJ under accession nos NW_021961 and NW_000207 respectively) (17). DNA (0.1 µg) was amplified with 0.75 U rTaq polymerase (Toyobo, Osaka, Japan) in 2 mM MgCl2 and the two primer pairs described above at 0.25 mM in a 25-µl reaction mixture. The PCR incubation conditions were 94°C for 4 min; 35 cycles of 93°C for 1 min, 60°C for 1 min and 72°C for 1 min; and a final incubation at 72°C for 7 min. These PCR products were subjected to electrophoresis on polyacrylamide gels and the absence of a product amplified with D4Mit237 (124 bp) in spite of the presence of a product amplified with D4Mit286 (76 bp) was taken to indicate that a mouse was a plt/plt homozygote. We further confirmed that in each putative plt/plt homozygote there was significant reduction of the number of Thy-1.2+ T cells in axillary, cervical and inguinal LN by using a flow cytometer (Epics XL; Coulter, Palo Alto, CA).
LPS injection
To activate epidermal LC, 7-week-old mice were injected with 20 µg of LPS from Escherichia coli 055:B5 (Difco, Detroit, MI) in 0.2 ml of PBS i.v. (18). Injection of 0.2 ml of PBS alone was used as a negative control. Four days after injection, mice were sacrificed under deep anesthesia with ether, and skin regional LN (axillary, brachial, inguinal), spleen, liver, lung and trunk skin were prepared for immunohistochemical and flow cytometric analyses. To observe the LC migration from the skin, 7- to 8-week-old BALB/c and plt/plt mice were injected with 20 µg of LPS, and 12 or 18 h after the injection the ear skin was prepared as described below.
Preparation of epidermal skin sheets
Epidermal skin sheets were prepared as described previously (5). Briefly, ear skin was mechanically divided into dorsal and ventral halves, and the dorsal half of the ear skin was floated with the dermal side down in 0.5 M ammonium thiocyanate (Wako, Osaka, Japan) at 37°C for 15 min to separate the epidermis and dermis. Epidermal sheets were fixed in acetone for 10 min, rehydrated in PBS for 5 min and immunostained with 5 µg/ml FITC-conjugated anti-mouse I-Ab/d mAb (25-9-17; PharMingen, San Diego, CA).
Immunohistochemistry
Tissue samples of skin regional LN (axillary, brachial and inguinal), spleen, liver and skin were frozen in OCT compound (Sakura Finetechnical, Tokyo, Japan). Sections were cut at 67 µm thickness, fixed with acetone for 10 min at room temperature, rehydrated with PBS and incubated with rat anti-mouse mAb against CD205 (DEC205) (NLDC145, 10 µg/ml) (a kind gift from Dr K. Inaba, Kyoto University), Macrosialin (19) (FA11, 5 µg/ml; Serotec, Oxford, UK), c-Kit (14) (ACK2, 5 µg/ml), Thy-1.2 (biotinylated 30-H12, 10 µg/ml; PharMingen) or B220 (FITC-conjugated RA3-6B2, 5 µg/ml; PharMingen) for characterizing lymphocytes and a goat anti-mouse polyclonal antibody against CCL21/SLC (6Ckine, 10 µg/ml; R & D, Minneapolis, MN) for detection of dermal lymphatics. Secondary antibody [goat anti-rat IgG (H + L) or rabbit anti-goat IgG (H + L); KPL, Gaithersburg, MD] and streptavidin-conjugated FITC or TRITC (Sigma, St Louis, MO) were used as necessary. Samples were sealed with Vectashield (Vector, Burlingame, CA) and observed using a fluorescent microscope system (BX60; Olympus, Japan). DEC205+, FA11+ and MG-laden cells stained by DEC205 and FA11 in the regional LN were counted per defined field area (0.106 mm2). A total of 10 fields were counted per specimen and the number of cells presented as the mean ± SD. Statistical significance was assessed by Students t-test.
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Results
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Normal steady-state LC/DC migration into LN in plt/plt-Mgf-Tg
C57BL/6-+/Mgf-Tg (Mgf-Tg) mice carrying full-length murine Mgf cDNA driven by the human cytokeratin 14 promoter display melanocytosis in the epidermis, but do not show any symptoms of mastocytosis or inflammatory responses (14,16). The skin regional LN are pigmented because TGF-ß1-dependent DC-lineage cells capture MG and traffic them to the regional LN, but melanocytes are not present there (16).
In plt/plt-Mgf-Tg double-mutant mice as well as +/plt-Mgf-Tg littermates, the proliferation of melanocytes in the epidermis and in pigmented skin regional LN is comparable to that in Mgf-Tg mice, as we have reported (14) (Fig. 1A and B). Since it has been reported that there are reduced DC numbers, as well as T cell numbers, in LN, in plt/plt mice (10) we examined these regional LN immunohistochemically. Surprisingly, skin regional LN in both +/plt-Mgf-Tg and plt/plt-Mgf-Tg contained MG-laden cells at almost the same levels (Fig. 2A and D). DEC205+ (DEC205+) DC and FA11+ (FA11+) macrophages also existed in regional LN of plt/plt-Mgf-Tg as well as those of +/plt-Mgf-Tg (Fig. 2B, C, E and F). Most MG-laden cells expressing FA11 contained more MG than those expressing DEC205 (Fig. 3A and B). Counting the number of DEC205+ DC and FA11+ macrophages revealed that the number of total and MG-laden DC and macrophages was comparable in +/plt-Mgf-Tg and plt/plt-Mgf-Tg (Fig. 3C). Approximately 25% of DEC205+ cells and 56% of FA11+ cells were laden with MG in both +/plt-Mgf-Tg and plt/plt-Mgf-Tg. These findings indicate that the antigen trafficking from the epidermis to regional LN was not impaired in plt/plt-Mgf-Tg under the steady-state condition.

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Fig. 1. Melanocytosis and pigmented skin regional LN in the plt/plt mouse carrying Mgf-Tg. (A) +/plt-Mgf-Tg: hyperproliferation of melanocytes in the epidermis (arrows in the left panel) and pigmented inguinal LN (middle panel) is shown. (B) plt/plt-Mgf-Tg shows findings the same as +/plt-Mgf-Tg. Other skin regional LN (cervical, brachial and axillary) were also pigmented (data not shown). Spleens were not pigmented in +/plt-Mgf-Tg or plt/plt-Mgf-Tg mice (right panels in A and B). (C) Littermates of +/plt and plt/plt-Mgf-Tg not carrying Mgf-Tg show no melanocytosis in epidermis and no pigmentation of regional LN. [Right panel: +/plt (left) and plt/plt (right) background.] Original magnification of skin: x132. Scales below LN and spleens: 1 mm.
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Fig. 2. Comparable numbers of MG-laden cells, DC and macrophages in skin regional LN of +/plt-Mgf-Tg and plt/plt-Mgf-Tg mice in the steady state. Skin regional LN of +/plt-Mgf-Tg and plt/plt-Mgf-Tg mice under the light field views (A and D) and stained with DEC205 (B and E, white) or FA11 (C and F, white). Figures showed inguinal or brachial LN. Arrows, capsule; f, B cell follicle; t, T cell zone. Original magnification: x33.
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Fig. 3. Comparable numbers of MG-laden DC and macrophages in skin regional LN of +/plt-Mgf-Tg and plt/plt-Mgf-Tg mice in the steady state. (A) MG-laden DEC205+ and (B) MG-laden FA11+ cells in regional LN (green-stained with arrows). A large DEC205 cell including numerous MG is indicated (white arrowhead in A). Numbers of DEC205+ cells and FA11+ cells, and those with MG (dotted bars) were counted using 10 views each of 0.106 mm2. The percentage of MG-laden cells in total DEC205+- or FA11+-stained cells was indicated in parentheses. Original magnification: x330. Two +/plt-Mgf-Tg mice (7 and 5 weeks old) and three plt/plt-Mgf-Tg mice (two 7 and one 5 weeks old) were observed in this experiment.
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No accumulation of MG was observed in spleen, Peyers patches, non-skin regional LN such as mesenteric LN or non-lymphoid organs in either +/plt- or plt/plt-Mgf-Tg (Fig. 1A and B, and data not shown), indicating that MG from the epidermis were trafficked to skin regional LN without draining into any other organ.
We confirmed that the pigmentation of regional LN is not due to melanocyte proliferation in the LN (Fig. 2) (16). Moreover, littermates of +/plt-Mgf-Tg and plt/plt-Mgf-Tg mice without the Mgf transgene did not show melanocytosis in the epidermis or pigmented regional LN (Fig. 1C), indicating that Mgf transgene expression was not affected by the plt mutation.
Impaired active-state LC/DC migration into LN in plt/plt-Mgf-Tg
To assess the antigen trafficking in the active state, we injected 20 µg of LPS to activate epidermal LC and observed skin regional LN 4 days after injection. Because systemic LPS injection is able to promote DC migration from non-lymphoid organs (18), we injected LPS i.v. and confirmed LC emigration out of epidermis (see later result). MG-laden cells were significantly increased in LPS-injected +/plt-Mgf-Tg (Fig. 4A and B), whereas these cells were not increased in plt/plt-Mgf-Tg (Fig. 4D and E). Less DEC205+ DC were observed in plt/plt-Mgf-Tg than in +/plt-Mgf-Tg (Fig. 4C and F).

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Fig. 4. MG-laden cells and DC are not increased in regional LN in plt/plt-Mgf-Tg by LPS injection. Inguinal or brachial LN of +/plt-Mgf-Tg treated with PBS (A) or LPS (B and C) and plt/plt-Mgf-Tg treated with PBS (D) or LPS (E and F). Light field views (A, B, D and E) and DEC205-stained (C and F, white) views of each specimen. f, B cell follicle; t, T cell zone. Original magnification: x33 (AD), x66 (E and F).
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We counted the number of DEC205+ DC and FA11+ macrophages in regional LN. Total and MG-laden DEC205+ DC were significantly increased in LPS-injected +/plt-Mgf-Tg, but not in plt/plt-Mgf-Tg (Fig. 5). MG-laden FA11+ macrophages were increased in +/plt-Mgf-Tg, whereas the total number of FA11+ macrophages was variable; in one of three examinations, they were not increased, while in the other two cases we observed 1.13- and 1.23-fold increases in LPS-injected mice (data not shown). In contrast, MG-laden macrophages in the plt/plt-Mgf-Tg mice were not increased in any of the examinations. These results indicate that the antigen trafficking into regional LN of plt/plt-Mgf-Tg mice was deficient under active-state conditions. Moreover, even in the active state, the trafficking of control mice might be done mainly by DC.

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Fig. 5. Increased number of MG-laden DC and macrophages in regional LN of +/plt-Mgf-Tg, but not in plt/plt-Mgf-Tg, in the active state. Cell numbers were counted 4 days after 20 µg LPS or PBS injection in brachial and inguinal LN. Left panel: total DEC205+ and FA11+ cell number. Right panel: MG-laden DEC205+ and FA11+ cell number. PBS (open bars)- and LPS (filled bars)-injected groups indicated. Each cell number was counted using 10 views, each of 0.106 mm2. Three 7-week-old mice were observed in each group except for LPS-injected plt/plt-Mgf-Tg (four mice) and representative data presented. *P < 0.01, **P < 0.001 between PBS- and LPS-injected mice. Significant differences were also observed between the LPS-injected +/plt-Mgf-Tg and LPS-injected plt/plt-Mgf-Tg: P < 0.001 in both total and MG-laden DEC205+ cell number; P = 0.0025 in total FA11+ cell number. MG-laden FA11+ cell number was not significantly different between the LPS-injected +/plt-Mgf-Tg and LPS-injected plt/plt-Mgf-Tg.
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Normal emigration of LC from skin in plt/plt-Mgf-Tg
Massive LC migration from the epidermis into regional LN was induced by LPS injection in +/plt-Mgf-Tg, but not in plt/plt-Mgf-Tg mice. To identify the defect of plt/plt antigen trafficking in the active state, we prepared epidermal sheets from plt/plt mice and their littermates carrying or not carrying Mgf-Tg at 12 or 18 h after LPS injection. I-A+ LC of plt/plt mice were decreased compared to those of their normal littermates in the epidermal sheets (Fig. 6B and D, and data not shown). This result indicates that LC of plt/plt mice migrated normally out of the epidermis in response to LPS injection, but might not reach the skin regional LN under the active-state conditions.

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Fig. 6. Normal emigration of LC from the epidermis of plt/plt mice. Epidermal sheets from the ear skin were stained with anti-I-Ab/d mAb. I-A+ LC (white) in the epidermis of BALB/c (A and B) or BALB/plt/plt (C and D). Epidermis 12 h after PBS injection (A and C) and 12 h (B and D) after LPS injection. Three plt/plt and one plt/plt-Mgf-Tg mice group were observed, and representative data presented. Original magnification: x33.
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To determine where the LC that captured MG in the skin were subsequently present, we searched for MG-laden cells in organs other than regional LN in the LPS-injected plt/plt-Mgf-Tg mice. In the spleens of some LPS-injected mice, there were only a few MG-laden DC and macrophages. Although we found a slight increase of MG-laden cells in the spleens of two of four LPS-injected plt/plt-Mgf-Tg mice, similar increases were also observed in one of three PBS-injected control mice. Such cells were not observed in the liver or lung (data not shown). Moreover, accumulation of MG-laden cells or DEC205+ DC was hardly observed around the lymphatics in the dermis, although a DC increase in the dermis was observed in only one of the plt/plt-Mgf-Tg mice examined here (data not shown).
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Discussion
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This study showed the presence of distinct mechanisms for antigen trafficking in the steady and active states. It is well known that LC migration from the skin is induced by various stimuli (3,11,12,18,2022) and that the migration pathway of the functionally mature LC via the lymphatic vessels is regulated by CCR7CCL21 signaling (68). These findings were mainly obtained by the application of stimulants or sensitizers, or in in vitro and ex vivo experiments. Considering the fact that cultured LC or LC in skin grafts appear to have an activated phenotype (2,5,12), phenomena might have been observed only in the activated-skin circumstances in these systems. Recently, we reported that the skin antigens were constitutively trafficked to skin regional LN even in the steady state (16). Using the same in vivo system, we showed here that there is a distinct pathway of antigen trafficking that is independent of CCR7CCL21 signaling under steady-state conditions.
In the steady state, MG-laden DEC205+ DC constituted
25% of total DEC205+ DC in skin regional LN in 5- to 7-week old mice (Fig. 3C). Since we think that the MG-laden DEC205+ DC in regional LN are descendants of LC, this result suggests that in the steady-state LN, at least a quarter of the total DEC205+ DC are migrated LC. Recently Ruedl et al. and Henri et al. suggested the possibility of the migration of LC, which were DEC205high in regional LN, from the skin even in the steady state (23,24). Our findings made by visualizing MG support this idea.
MG-laden FA11+ macrophages appeared to bear more MG than MG-laden DEC205+ DC (Fig. 3A and B). We speculated in our previous work that since antigen-carrying LC descendants are probably short lived, they die in LN, most likely by apoptosis, and subsequently they are phagocytosed by resident macrophages. The accumulation of MG in macrophages shown in this work appears to support this proposal. In +/plt-Mgf-Tg, MG-laden FA11+ cells were increased, but the total number of FA11+ cells was not increased in the active state. Additionally, in plt/plt-Mgf-Tg, MG-laden FA11+ cells were not increased in the active state, indicating that macrophages might not contribute greatly to carrying antigens from the skin even in the active state (25), further supporting the idea that DC lineage cells carry antigens and resident macrophages in LN may capture the descendant cells.
Activation of LC in plt/plt-Mgf-Tg by i.v. LPS injection did not result in an accumulation of MG-laden DC in regional LN despite the fact that LC emigration from the skin occurred normally (Figs 5 and 6). This observation is in agreement with the report that normal LC/DC emigration was observed in plt/plt mice in skin organ cultures (10). We considered two possible destinations of the LC that migrated from the epidermis in LPS-injected plt/plt-Mgf-Tg: (i) the emigrated LC may be delivered to various organs such as the spleen, liver or lung via the blood circulation and (ii) the emigrated LC may accumulate around or in the lymphatics, where CCL21-Leu is expressed (26) in the dermis. It has been reported that the T cell immune response was primed in the spleens of plt/plt mice, although this reaction was delayed compared with that of normal mice (27). This result indicated the delivery of antigen/antigen-presenting cells via the blood circulation. Therefore, we examined various organs of LPS-injected plt/plt-Mgf-Tg, but failed to find significant accumulation of MG-laden DC in specific organs such as the spleen, although a slight increase of MG-laden cells was observed in a few mice. In this study, the injection of 20 µg of LPS might not have been sufficient to induce significant DC accumulation in these organs. We were also not able to find apparent accumulation of MG-laden cells around or in the lymphatic vessels, or a significant increase of these cells in the dermis. MG-laden LC might migrate too diffusely to be detectable, suggesting that specific migration in the active state is defective in CCR7CCL21-Ser signaling-deficient mice.
The molecule(s) that regulate LC migration in the steady state remain(s) unknown. The molecular mechanism must involve molecules other than CCR7CCL21. LC migration has been reported to be modulated by the interaction of various molecules, including pro-inflammatory cytokines, chemokines, adhesion molecules and proteases (8,2835). It was also reported that an immunosuppressant regulated lymphocyte homing in a CCR7-independent manner (36). Additionally, we observed in the steady state that DEC205+ DC were distributed in some T cell area of the plt/plt-Mgf-Tg regional LN (Fig. 2E). This suggested the presence of regulatory molecules of LC/DC migration in the steady state. This in vivo system using hyperpigmented mice enabled us to analyze LC/DC migration from the skin in the steady and active states, and the mobilization of antigen-captured cells in LN or other organs.
We previously showed that antigen trafficking from the skin into regional LN was completely abolished in TGF-ß1-deficient mice, which lack LC and also antigen-transporting dermal DC (16,37), and which suffer from fulminating autoimmune disease (16,38). We demonstrated here that in plt/plt mice, which do not suffer from autoimmune disease, antigen trafficking is abolished only in the active state, but not in the steady state. Considering these results, continual trafficking of antigen into regional LN in the steady state might be a system for regulating self-reactivity.
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Acknowledgements
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We thank Dr Makoto Naito (Niigata University, Japan), Dr Kayo Inaba and Dr Yoshiki Omatsu (Kyoto University), and Dr Toshiyuki Yamane (Stanford University, Tottori University) for helpful suggestions and technical instruction. We also thank Dr Toshiyuki Shibahara (Tottori University) for maintenance of mice and Ms Toshie Shinohara for secretarial assistance. This work was supported by grants from the Special Coordination Funds for promoting Science and Technology from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government.
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Abbreviations
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DCdendritic cell
DECdendritic epidermal cell
LCLangerhans cell
LNlymph node
LPSlipopolysaccharide
Mgf-Tgmast cell growth factor transgene
MGmelanin granule
pltpaucity of lymph node T cell
SLCsecondary lymphoid chemokine
Tgtransgene
TGFtransforming growth factor
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