Cutting Edge: Langerin+ Dendritic Cells in
the Mesenteric Lymph Node Set the Stage for
Skin and Gut Immune System Cross-Talk
This information is current as
of July 28, 2017.
Sun-Young Chang, Hye-Ran Cha, Osamu Igarashi, Paul D.
Rennert, Adrien Kissenpfennig, Bernard Malissen,
Masanobu Nanno, Hiroshi Kiyono and Mi-Na Kweon
J Immunol 2008; 180:4361-4365; ;
doi: 10.4049/jimmunol.180.7.4361
http://www.jimmunol.org/content/180/7/4361
Subscription
Permissions
Email Alerts
This article cites 21 articles, 10 of which you can access for free at:
http://www.jimmunol.org/content/180/7/4361.full#ref-list-1
Information about subscribing to The Journal of Immunology is online at:
http://jimmunol.org/subscription
Submit copyright permission requests at:
http://www.aai.org/About/Publications/JI/copyright.html
Receive free email-alerts when new articles cite this article. Sign up at:
http://jimmunol.org/alerts
The Journal of Immunology is published twice each month by
The American Association of Immunologists, Inc.,
1451 Rockville Pike, Suite 650, Rockville, MD 20852
Copyright © 2008 by The American Association of
Immunologists All rights reserved.
Print ISSN: 0022-1767 Online ISSN: 1550-6606.
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
References
OF
THE
JOURNAL IMMUNOLOGY
CUTTING EDGE
Cutting Edge: Langerinⴙ Dendritic Cells in the
Mesenteric Lymph Node Set the Stage for Skin and Gut
Immune System Cross-Talk1
Sun-Young Chang,* Hye-Ran Cha,* Osamu Igarashi,† Paul D. Rennert,‡
Adrien Kissenpfennig,§ Bernard Malissen,§ Masanobu Nanno,¶ Hiroshi Kiyono,† and
Mi-Na Kweon2*
ranscutaneous immunization (TCI)3 is a novel needlefree vaccination method that induces an immune response through the topical application of a vaccine Ag
and adjuvant to the intact skin surface (1). When used with
cholera toxin (CT) or heat-labile enterotoxin as adjuvant, TCI
with heterologous protein induces robust serum IgG and secretory IgA (SIgA) Ab responses against both toxins and coadministered Ag in both the systemic and mucosal immune systems
without systemic toxicity in human trials (2, 3). Such findings
highlight the importance of this novel strategy for the induction
T
*Mucosal Immunology Section, International Vaccine Institute, Seoul, Republic of Korea;
†
Division of Mucosal Immunology, Department of Microbiology and Immunology, The
Institute of Medical Science, The University of Tokyo, Tokyo, Japan; ‡Biogen Idec, Inc.,
Cambridge, MA; §Centre d’Immunologie de Marseille-Luminy, Institut National de la
Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de la Méditerranée, Parc Scientifique et Technologique de Luminy, Marseille, France.
¶
Yakult Central Institute for Microbiological Research, Tokyo, Japan
Received for publication November 19, 2007. Accepted for publication February
11, 2008.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
1
This work was supported by the governments of the Republic of Korea, Sweden, Japan,
and Kuwait, by a Korean Research Foundation Grant funded by the Korean government
www.jimmunol.org
of mucosal IgA Abs using intact skin as well as mucosal surfaces.
However, the mechanism by which mucosal immune responses
are induced via skin immunization has remained elusive. Our
finding that TCI induced intestinal SIgA Abs suggests a possible linkage between the skin and gut immune responses, leading
us to focus our study on the elucidation of that linkage.
Materials and Methods
Mice
C57BL/6 mice were purchased from the Charles River Laboratories. To generate mice lacking both Peyer’s patches (PP) and lymph nodes (LN), pregnant
mice were injected i.v. with 200 ␮g of lymphotoxin-␤ receptor (LT␤R)-Ig and
200 ␮g of TNFR55-Ig on gestational days 14 and 17 (4). To generate the PPnull mice, pregnant mice were injected i.v. with 600 ␮g of anti-IL-7R␣ mAb on
gestational day 14 (5). Langerin-diphtheria toxin receptor (DTR) and polymeric Ig receptor (pIgR)⫺/⫺ mice were used (6, 7). Vitamin A-deficient
C57BL/6 mice were prepared as previously reported (8).
Immunization
Mice were immunized transcutaneously as described elsewhere (9). Briefly, an
occlusive patch was applied to the shaved dorsum of each mouse for 24 h. The
patch, which contained gauze soaked in 100 ␮g of tetanus toxoid (TT) plus 50
␮g of CT (List Biological Laboratories), served as a delivery device for the Ag
and adjuvant while also preventing the mice from disturbing the gauze. Once
the gauze was removed, the mice were thoroughly washed and dried to prevent
any oral contamination due to grooming. To analyze the induction of mucosal
immune responses, mice were immunized by TCI three times at 2-wk intervals.
TT was provided by Dr. Y. Higashi (Biken Foundation, Osaka University,
Osaka, Japan).
Flow cytometry
Anti-CD205-biotin (clone NLDC-45; BMA Biomedicals) and anti-langerinAlexa Fluor 488 (clone 929F3; AbCys) were used in accordance with the manufacturers’ instructions. Other Abs were purchased from BD Pharmingen. For
staining of the B subunit of CT (CTB)86 –103-I-Ab tetramers, CT-I-Ab tetramers were formed by incubation of CT-I-Ab monomers and streptavidin-PE
(KRF-2005-015-E00117), and by grants from the Ministry of Education, Science, Sports,
and Culture and Ministry of Health and Labor in Japan.
2
Address correspondence and reprint requests to Dr. Mi-Na Kweon, Mucosal Immunology Section, International Vaccine Institute, Seoul National University Research Park,
Kwanak-Gu, Seoul, Republic of Korea 151-818. E-mail address: [email protected]
3
Abbreviations used in this paper: TCI, transcutaneous immunization; ASC, Ab-secreting
cell; BM, bone marrow; CLN, cutaneous lymph node; CT, cholera toxin; CTB, B subunit
of CT; DC, dendritic cell; DT, diphtheria toxin; DTR, diphtheria toxin receptor; LC,
Langerhans cell; LI, large intestine; LN, lymph node; LT␤R, lymphotoxin-␤ receptor;
MLN, mesenteric lymph node; MNC, mononuclear cell; pIgR, polymeric Ig receptor; PP,
Peyer’s patch; RA, retinoic acid; SI, small intestine; SIgA, secretory IgA; SP, spleen; TT,
tetanus toxoid.
Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
Topical transcutaneous immunization (TCI) presents
many clinical advantages, but its underlying mechanism
remains unknown. TCI induced Ag-specific IgA Ab-secreting cells expressing CCR9 and CCR10 in the small intestine in a retinoic acid-dependent manner. These intestinal IgA Abs were maintained in Peyer’s patch-null mice
but abolished in the Peyer’s patch- and lymph node-null
mice. The mesenteric lymph node (MLN) was shown to be
the site of IgA isotype class switching after TCI. Unexpectedly, langerinⴙCD8␣ⴚ dendritic cells emerged in the
MLN after TCI; they did not migrate from the skin but
rather differentiated rapidly from bone marrow precursors. Depletion of langerinⴙ cells impaired intestinal IgA
Ab responses after TCI. Taken together, these findings suggest that MLN is indispensable for the induction of intestinal IgA Abs following skin immunization and that crosstalk between the skin and gut immune systems might be
mediated by langerinⴙ dendritic cells in the MLN. The
Journal of Immunology, 2008, 180: 4361– 4365.
4362
CUTTING EDGE: CROSS-TALK BETWEEN THE SKIN AND GUT IMMUNE SYSTEMS
(Molecular Probe) with a molecular ratio of 5:1 for 2 h followed by incubation
with cells for 2.5 h at 37°C in the CO2 incubator.
Cell preparation
Mononuclear cells (MNC) were dissociated from the lamina propria of the
small intestine (SI) and the large intestine (LI) by digestion using a collagenase/
DNase I enzyme solution after the removal of PP. Cells were then enriched by
a discontinuous density gradient containing 40 and 75% Percoll (Amersham
Bioscience).
ELISPOT
The number of Ag-specific Ab-secreting cells (ASC) was determined by an
ELISPOT assay according to an established protocol (10) with the aid of a stereomicroscope (SZ2-ILST; Olympus). The number of Ag-specific ASCs was
standardized by the total MNCs because similar numbers of total IgA and IgG
ASCs were observed in naive and TCI-immunized mice.
Chemotaxis assay
To evaluate the expression of chemokine receptors on Ag-specific ASCs, a chemotaxis assay and ELISPOT were combined as previously described (11).
Transplant of congenic bone marrow (BM) cells
Statistical analysis
Data are expressed as the mean ⫾ SD. Statistical comparison between experimental groups was performed using the Student t test.
Results and Discussion
TCI induces intestinal IgA Abs in a retinoic acid-dependent manner
To investigate the interaction between skin and mucosal immunity, we administered TT as Ag and CT as mucosal adjuvant via
TCI. TCI elicited TT-specific IgA and IgG Abs in the fecal extracts as well as sera (Fig. 1A). In addition, other mucosal secretions, including saliva and vaginal and nasal washes, were also
found to contain significant levels of TT-specific IgA Abs. As
expected from these Ab results, a high number of TT-specific
ASCs were detected in the lamina propria of the SI and LI after
TCI with TT and CT (Fig. 1B). In contrast, three parenteral
immunizations (s.c. or i.p.) induced no Ag-specific ASCs in the
gut (data not shown). To determine whether the TCI-induced
IgA ASCs secreted SIgA Abs associated with the secretory component, IgA Ab responses after TCI were analyzed in pIgR⫺/⫺
mice lacking this IgA secretion pathway (7). These mice showed
complete loss of IgA in the fecal extracts and saliva, while levels
of IgG Abs remained comparable to those seen in wild-type
mice (Fig. 1C). This result demonstrates that TCI can elicit the
formation and secretion of SIgA into mucosal compartments.
To identify the expression of chemokine receptors on the
TCI-induced intestinal Ag-specific IgA ASCs, we used a technique that combined chemotaxis assay and ELISPOT. CTBand TT-specific IgA ASCs migrated to TECK/CCL25,
CTACK/CCL27, or MEC/CCL28 (Fig. 1D), showing that
these cells expressed functional CCR9 and CCR10 and confirming previous observations of polyclonal IgA-ASCs (13, 14).
Intestinal dendritic cells (DCs) imprint gut-homing specificity on lymphocytes by retinoic acid (RA) (8); reciprocally, DCs
from peripheral LNs imprint skin-homing specificity on T cells
by vitamin D3 (15). In B cells, RA acts synergistically with IL-6
or IL-5 to induce IgA secretion (16). Therefore, most skin DCs
are expected to induce activated Ag-specific T and B cells to
home to the skin after TCI. However, TT-specific IgA ASCs in
the gut were dramatically reduced in vitamin A-deficient mice
FIGURE 1. RA-dependent induction of intestinal IgA Abs by TCI. A, Mice
received three TCIs with TT plus CT. At day 7, after the final TCI, TT-specific
Abs were measured in the sera and various mucosal secretions. The level of Ab
production was shown as the reciprocal log2 titer. B, TT-specific ASCs per 106
MNCs were determined using ELISPOT. Results are representative of at least
five experiments. ND, not detected. C, TT-specific IgG or IgA Abs were determined from pIgR⫺/⫺ mice after TCI. Results are shown from two independent
experiments. D, After chemotaxis assay using MNCs of SI following TCI, the
number of Ag-specific IgA ASCs among the cells that had migrated into each
chemokine was determined by using an ELISPOT. The data represent the percentage of Ag-specific IgA ASCs that migrated into each chemokine relative to
total Ag-specific IgA ASCs. Representative data from two separate experiments
are shown, compared with medium. TECK, thymus-expressed chemokine;
CTACK, cutaneous T cell-attracting chemokine; MEC, mucosae-associated
epithelial chemokine. E, TT-specific IgA ASCs from the vitamin A-sufficient
(⫹) and vitamin A-deficient (⫺) mice were determined after TCI. Results are
representative of at least two experiments. ⴱ, p ⬍ 0.01; ⴱⴱ, p ⬍ 0.001; ⴱⴱⴱ, p ⬍
0.0001.
after TCI (Fig. 1E). This finding implies the existence of a
unique subset of DCs after skin immunization that can induce
homing of IgA ASCs into the gut in an RA-dependent manner.
Mesenteric lymph node (MLN) is indispensable for the induction of
intestinal IgA ASCs after TCI
To evaluate the induction of Ag-specific CD4⫹ T cells by TCI,
we used tetramer staining of the CT peptide-MHC class II
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
Eight-week-old recipient CD45.2⫹ C57BL/6 mice were lethally irradiated
with 950 rad by a Gammacell low dose-rate research irradiator (GC 3000 Elan;
MDS Nordion) and were transferred i.v. with BM cells (1 ⫻ 106) obtained
from congenic CD45.1⫹ C57BL/6 mice as described previously (12).
The Journal of Immunology
complex. Increased levels of CT-specific CD4⫹ T cells were detected by day 12 after TCI in the spleen, the skin-draining cutaneous lymph node (CLN), and the MLN (Fig. 2A). In contrast, no CT-specific CD4⫹ T cells were found in either PP or
SI. When TCI was combined with FTY720 to prevent the recirculation of T lymphocytes, Ag-specific CD4⫹ T cells were
also activated in the spleen, CLN, and MLN (Fig. 2B), showing
that CD4⫹ T cells are primed directly by Ag-bearing DCs in
these tissues rather than by passive diffusion through blood circulation. We next sought to determine where IgA class switching occurs after TCI by using FTY720 treatment to confine the
ASCs to the organ of isotype class switching (17). FTY720
treatment increased the number of IgA ASCs in the MLN and
IgG ASCs in the CLN and reduced IgA ASCs in the SI (Fig.
2C). To identify the privileged sites for induction of intestinal
IgA Abs after TCI, we used mice that lacked PP as well as mice
that lacked both LN and PP but retained isolated lymphoid
follicles. After TCI, Ag-specific IgA ASCs were maintained
in the gut of the PP-null mice (Fig. 2D). However, the gut of
the LN- and PP-null mice was bereft of IgA ASCs after TCI
(Fig. 2E). Taken together, these results strongly suggest that
the MLN, rather than PP or CLN, is the privileged site for
the induction of intestinal IgA responses after TCI. The
MLN seems to hold a central position in immune anatomy,
acting as a border between the gut and systemic immune
systems.
Emergent langerin⫹ DCs in the MLN are key to the induction of
intestinal IgA Abs after TCI
To investigate the mechanism underlying the induction of
intestinal IgA by TCI, we next focused on the DCs. Langerin
has been regarded as a specific marker of epidermal Langerhans cells (LCs) (18). Langerin⫹ DCs make up 30 –50% of
the total CD11c⫹ DCs in the CLN (Fig. 3A). Strikingly,
distinct CD205⫹langerinhigh DCs appeared in the MLN after TCI but not at steady-state conditions (Fig. 3A). Langerin⫹ DCs in mice can be classified into tissue-derived LCs
and blood-derived langerinlowCD8␣⫹ DCs (6). Interestingly, the novel langerin⫹ DCs in the MLN did not express
CD8␣ but expressed CD11b (Fig. 3A), suggesting that langerin⫹ DCs in the MLN after TCI closely resemble migratory tissue-derived LCs but not blood-derived DCs. To further characterize these emergent langerin⫹ DCs in the MLN
after TCI, we compared the expression patterns of costimulatory molecules and gut-homing integrins in the epidermis,
CLN, and MLN (Fig. 3B). Interestingly, the levels of CD80,
CD86, and CD40 expressed on langerin⫹ DCs in the MLN
were comparable to those in the CLN after TCI, but expression of gut homing-related integrins such as CCR9, ␣4␤7,
and CD103 (␣E), were higher in the langerin⫹ DCs of the
MLN than in those of the CLN.
To investigate the origin of langerin⫹ DCs in the MLN after
TCI, we used LC chimeras, showing that recipient skin LCs
become resistant to irradiation (12). At 8 wk after a congenic
BM transplant, the presence of langerin⫹ DCs in the MLN was
evaluated after TCI. Langerin⫹ DCs, most of which were
CD45.1⫹ donor-derived cells, emerged in the MLN but not in
the spleen and PP (Fig. 3C). Regardless of TCI, ⬃90% of langerin⫹ DCs in the CLN were also CD45.1⫹ donor-derived
cells. These results suggest that epidermal LCs can be resistant
to irradiation, but most langerin⫹ DCs in the LN are replenished from BM-derived precursors. Recent articles have identified a novel population of circulating langerin⫹ DCs in the
dermis, skin-draining LN, and lung; this population is donorderived and does not originate in the epidermal LC (19 –21).
Their recruitment into the LN requires CCR7. After TCI, langerin⫹ DCs of the MLN closely resemble dermal circulating
langerin⫹ DCs. In this regard, TCI-induced intestinal IgA responses were significantly decreased, but serum IgG and IgA Ab
levels were maintained in the CCR7⫺/⫺ mice (data not shown),
suggesting that Ag trafficking to the MLN is tightly regulated
by CCR7 signaling. Circulating langerin⫹ DCs and the TCIinduced langerin⫹ DC population in MLN express CD103
whereas epidermal LCs do not. In addition, we challenged mice
by painting tetramethylrhodamine isothiocyanate (TRITC)
and CT on the skin but could not find any TRITC⫹langerin⫹
DCs in the MLN (data not shown). Therefore, we speculate
that circulating langerin⫹ DCs could rapidly differentiate in or
migrate to the MLN in a CCR7-dependent manner after TCI.
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
FIGURE 2. Essential role of MLN for the induction of intestinal IgA ASCs
after TCI. A, MNCs were stained with CT-I-Ab tetramer at day 12 after a single
TCI. The numbers represent the percentage of CT-I-Ab tetramer⫹CD4⫹ T
cells relative to total CD4⫹ T cells. B, Mice were treated i.p. with FTY720 (1
mg/kg) every other day from 1 day before TCI. MNCs were stained with CTI-Ab tetramer at day 12 after a single TCI. Data are representative of at least five
experiments. C, The numbers of TT-specific IgA and IgG ASCs were measured
at day 12 after a single TCI with FTY720 treatment. Representative data from
three separate experiments are shown. ⴱ, p ⬍ 0.01, compared with group
treated with PBS instead of FTY720. D and E, TT-specific IgA ASCs was evaluated in the PP-null progeny treated with anti-IL-7R␣ mAb in utero (D) and in
the LN- and PP-null progeny treated with TNFR55-Ig and LT␤R-Ig in utero
(E) at day 7 following the final of three TCIs. Results are representative of two
independent experiments. ⴱ, p ⬍ 0.01.
4363
4364
CUTTING EDGE: CROSS-TALK BETWEEN THE SKIN AND GUT IMMUNE SYSTEMS
Inflammation signals, such as CT, could favor differentiation of
BM precursors into langerin⫹ DCs. The precise mechanism
underlying this alternative possibility is currently under investigation in our laboratory.
We used langerin-DTR knock-in mice to determine
whether intestinal IgA responses could be induced by TCI in
the absence of langerin⫹ DCs of MLN (6). In the langerinDTR mice, diphtheria toxin (DT) depleted 98 –99% of langerin⫹ DCs in the skin and CLN at day 2 after injection
(data not shown). When langerin-DTR mice were immunized by TCI together with DT treatment, the level of TTspecific SIgA Abs in the fecal extracts was significantly decreased in the absence of langerin⫹ DCs, while the levels of
IgG and IgA Abs in the sera remained unchanged (Fig. 3D).
Consistent with this, the number of TT-specific IgA ASCs in
the SI was also significantly reduced after in vivo ablation of
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
FIGURE 3. Emergent
langerin⫹
DCs in the MLN was important for
TCI-induced intestinal IgA responses.
A and B, The langerin⫹ population
gated from CD11c⫹ DCs was analyzed
at day 3 after TCI and compared with
naive mice (N). Representative data
from at least five separate experiments
are shown. C, CD45.2⫹ WT C57BL/6
mice were lethally irradiated and transferred i.v. with congenic CD45.1⫹ BM
cells. Eight weeks after BM transplant,
chimeric mice received TCI with 100
␮g of CT. The congenic marker expression of langerin⫹ DC was analyzed at
day 3 after TCI or without TCI. Representative data from three separate experiments are shown. D and E, To induce in vivo ablation of langerin⫹ DCs,
langerin-DTR (Lang-DTR) and WT
mice (Wt B6) were i.p. injected with 1
␮g of DT 2 days before and again 2
days after TCI. At day 7 after the final
of three TCIs, TT-specific Abs (D) and
TT-specific ASCs (E) were determined.
Representative data from three separate
experiments are shown. ⴱ, p ⬍ 0.01; ⴱⴱ,
p ⬍ 0.001.
langerin⫹ DCs (Fig. 3E). These results suggest that intestinal IgA Ab responses following TCI cannot occur in the absence of langerin⫹ DCs whereas IgG Ab responses can, due
to the compensation provided by other DCs. Collectively,
these findings suggest that langerin⫹ DCs are indispensable
for the induction of intestinal IgA Abs following TCI.
In summary, we have identified a novel mechanism underlying the induction of intestinal IgA Ab responses after TCI; langerin⫹ DCs in the MLN are indispensable for the RA-dependent induction of intestinal IgA Abs following TCI. Such a
connection is plausible, because skin and mucosal surfaces share
some immunological similarities, not the least of which is that
both are constantly exposed to the outside environment. Taken
together, our results suggest a new paradigm for cross-talk
between the skin and gut immune systems, one in which langerin⫹ DCs in the MLN play a key role.
The Journal of Immunology
Acknowledgments
We thank Drs. Makoto Iwata (Tokushima Bunri University, Tokushima, Japan) and Masafumi Yamamoto (Nihon University, Matsudo, Japan) for generous gifts of reagents and helpful discussions.
Disclosures
The authors have no financial conflict of interest.
References
10. Czerkinsky, C. C., L.A. Nilsson, H. Nygren, O. Ouchterlony, and A. Tarkowski.
1983. A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration
of specific antibody-secreting cells. J. Immunol. Methods 65: 109 –121.
11. Chang, S. Y., H. R. Cha, S. Uematsu, S. Akira, O. Igarashi, H. Kiyono, and
M. N. Kweon. 2008. Colonic patches direct the cross-talk between systemic compartments and large intestine independently of innate immunity. J. Immunol. 180:
1609 –1618.
12. Merad, M., M. G. Manz, H. Karsunky, A. Wagers, W. Peters, I. Charo,
I. L. Weissman, J. G. Cyster, and E. G. Engleman. 2002. Langerhans cells renew in the
skin throughout life under steady-state conditions. Nat. Immunol. 3: 1135–1141.
13. Bowman, E. P., N. A. Kuklin, K. R. Youngman, N. H. Lazarus, E. J. Kunkel, J. Pan,
H. B. Greenberg, and E. C. Butcher. 2002. The intestinal chemokine thymus-expressed chemokine (CCL25) attracts IgA antibody-secreting cells. J. Exp. Med. 195:
269 –275.
14. Kunkel, E. J., C. H. Kim, N. H. Lazarus, M. A. Vierra, D. Soler, E. P. Bowman, and
E. C. Butcher. 2003. CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells. J. Clin. Invest. 111: 1001–1010.
15. Sigmundsdottir, H., J. Pan, G. F. Debes, C. Alt, A. Habtezion, D. Soler, and
E. C. Butcher. 2007. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T
cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8: 285–293.
16. Mora, J. R.,. M. Iwata, B. Eksteen, S. Y. Song, T. Junt, B. Senman, K. L. Otipoby,
A. Yokota, H. Takeuchi, P. Ricciardi-Castagnoli, et al. 2006. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314: 1157–1160.
17. Cyster, J. G. 2005. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23: 127–159.
18. Valladeau, J., O. Ravel, C. Dezutter-Dambuyant, K. Moore, M. Kleijmeer, Y. Liu,
V. Duvert-Frances, C. Vincent, D. Schmitt, J. Davoust, et al. 2000. Langerin, a novel
C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the
formation of Birbeck granules. Immunity 12: 71– 81.
19. Bursch, L. S., L. Wang, B. Igyarto, A. Kissenpfennig, B. Malissen, D. H. Kaplan, and
K. A. Hogquist. 2007. Identification of a novel population of Langerin⫹ dendritic
cells. J. Exp. Med. 204: 3147–3156.
20. Ginhoux, F., M. P. Collin, M. Bogunovic, M. Abel, M. Leboeuf, J. Helft, J. Ochando,
A. Kissenpfennig, B. Malissen, M. Grisotto, et al. 2007. Blood-derived dermal langerin⫹ dendritic cells survey the skin in the steady state. J. Exp. Med. 204: 3133–3146.
21. Poulin, L. F., S. Henri, B. de Bovis, E. Devilard, A. Kissenpfennig, and B. Malissen.
2007. The dermis contains langerin⫹ dendritic cells that develop and function independently of epidermal Langerhans cells. J. Exp. Med. 204: 3119 –3131.
Downloaded from http://www.jimmunol.org/ by guest on July 28, 2017
1. Glenn, G. M., M. Rao, G. R. Matyas, and C. R. Alving. 1998. Skin immunization
made possible by cholera toxin. Nature 391: 851.
2. Glenn, G. M., T. Scharton-Kersten, R. Vassell, C. P. Mallett, T. L. Hale, and
C. R. Alving. 1998. Transcutaneous immunization with cholera toxin protects mice
against lethal mucosal toxin challenge. J. Immunol. 161: 3211–3214.
3. Glenn, G. M., D. N. Taylor, X. Li, S. Frankel, A. Montemarano, and C. R. Alving.
2000. Transcutaneous immunization: a human vaccine delivery strategy using a patch.
Nat. Med. 6: 1403–1406.
4. Rennert, P. D., J. L. Browning, R. Mebius, F. Mackay, and P. S. Hochman. 1996.
Surface lymphotoxin ␣/␤ complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184: 1999 –2006.
5. Yoshida, H., K. Honda, R. Shinkura, S. Adachi, S. Nishikawa, K. Maki, K. Ikuta, and
S. I. Nishikawa. 1999. IL-7 receptor ␣⫹CD3⫺ cells in the embryonic intestine induces the organizing center of Peyer’s patches. Int. Immunol. 11: 643– 655.
6. Kissenpfennig, A., S. Henri, B. Dubois, C. Laplace-Builhe, P. Perrin, N. Romani,
C. H. Tripp, P. Douillard, L. Leserman, D. Kaiserlian, 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.
7. Shimada, S., M. Kawaguchi-Miyashita, A. Kushiro, T. Sato, M. Nanno, T. Sako,
Y. Matsuoka, K. Sudo, Y. Tagawa, Y. Iwakura, and M. Ohwaki. 1999. Generation of
polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA. J. Immunol. 163: 5367–5373.
8. Iwata, M., A. Hirakiyama, Y. Eshima, H. Kagechika, C. Kato, and S. Y. Song. 2004.
Retinoic acid imprints gut-homing specificity on T cells. Immunity 21: 527–538.
9. Belyakov, I. M., S. A. Hammond, J. D. Ahlers, G. M. Glenn, and J. A. Berzofsky.
2004. Transcutaneous immunization induces mucosal CTLs and protective immunity by migration of primed skin dendritic cells. J. Clin. Invest. 113: 998 –1007.
4365