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BRIEF DEFINITIVE REPORT |
CORRESPONDENCE Daniel H. Kaplan: dankaplan{at}umn.edu
 Top ABSTRACT RESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Langerhans cells (LCs) are a long-lived subset of tissue DCs that reside in the epidermis (1). LCs acquire skin antigens, and then migrate to skin-draining LNs in both inflammatory and steady-state conditions (2, 3). LCs are derived from colony-stimulating factor-1 (CSF1)–dependent precursors that originate in the BM and migrate to the dermis before becoming fully differentiated and populating the epidermis (4, 5). LC development is affected by TGFß1. BM cells cultured in granulocyte/macrophage CSF and TGFß1 generate LC-like cells, and LCs are absent from TGFß1–/– mice (6–8).
In vivo, TGFß1 is secreted by leukocytes and nonhematopoietic cells, including keratinocytes, and has a pleiotropic role in the immune system (9). There are three isoforms of TGFß, but TGFß1 is the dominant isoform within the immune system. TGFß1 binds to the TGFß receptor II (TGFßRII) and ALK5 to activate Smad 2, 3, and 4.
Although it is clear that LC development requires TGFß1, the identity of the cell types responsible for secreting TGFß1, and whether TGFß1 acts directly on LCs or via an intermediary cell type, is unresolved. In BM chimeric experiments, TGFß1+/– severe combined immunodeficient BM cells transferred into irradiated TGFß1–/– severe combined immunodeficient mice are able to produce LCs (10). Thus, TGFß1 derived from nonhematopoietic cells in the skin, such as keratinocytes, is not required, and secretion by a cell of hematopoietic origin is sufficient for LC development. However, BM cells from TGFß1–/– mice were also able to generate donor-derived LCs when introduced into irradiated WT recipients, suggesting that nonhematopoietic sources of TGFß1 are sufficient to promote LC development (11). Interestingly, intradermal, but not intravenous, introduction of TGFß1 into TGFß1–/– mice led to LC development, which suggests that TGFß1 acts on LC precursors within the skin (10). Thus, neither hematopoietic nor skin-derived TGFß1 was required for LC development in these models, which leaves the source of TGFß1 that drives LC development unresolved.
To more definitively define the mechanisms by which TGFß promotes LC development in vivo, we developed two lines of mice that have a LC-specific deletion of either the gene for TGFß1 or TGFßRII, thereby generating mice with LC precursors that cannot secrete or respond to the cytokine, respectively.
To validate that Cre expression was restricted to LCs, Langerin-Cre mice were bred to Rosa26-enhanced GFP (EGFP) mice that have EGFP inserted into a ubiquitously expressed genomic locus behind floxed "stop" sequences (17). Cre activity deletes the stop sequences, thereby allowing EGFP expression only in those cells that express the Cre transgene. To quantify the number of LCs expressing the Cre transgene, we examined epidermal single-cell suspensions by flow cytometry. As expected, all epidermal MHC-II+, CD11c+ LCs from Langerin-Cre+ Rosa26-EGFPf/f mice showed expression of EGFP (Fig. 1 A, left, thick line). In contrast, EGFP was expressed only in a small subset of MHC-II+ cells in dermal single-cell suspensions (Fig. 1 A, right).
These EGFP+ cells are likely either LC precursors that reside in the dermis or epidermal LCs in the process of migrating though the dermis to regional LNs. EGFP+ cells were not observed in littermate control mice.
RESULTS AND DISCUSSION
Top
ABSTRACT
RESULTS AND DISCUSSION
MATERIALS AND METHODS
REFERENCES
Generation and validation of Langerin-Cre mice
To generate a mouse with selective expression of Cre recombinase in LCs, we used a genomic bacterial artificial chromosome (BAC) transgenic system similar to one we recently developed to express diphtheria toxin in LCs (12). The human genomic BAC RP11-504o1 contains the gene for Langerin, which is expressed by fully developed LCs (13, 14). Transgenic mice made with this BAC express Langerin specifically in epidermal LCs (12). The gene for a mammalian codon-optimized version of Cre was inserted into the BAC DNA just after the start ATG codon in exon I of Langerin using homologous recombination (Fig. S1 A, available at http://www.jem.org/cgi/content/full/jem.20071401/DC1) (15, 16). The correct insertion of Cre into exon I was confirmed by PCR (not depicted) and by restriction digest (Fig. S2). A 72-kb NotI fragment of this modified BAC was used to generate a single Langerin-Cre transgenic founder from 20 live births. Langerin-Cre mice are indistinguishable from littermate controls and have normal numbers of LCs, dermal DCs, other DC subtypes, and B and T cells in their spleen and LN (unpublished data).
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– and DEC-205bright, which is consistent with their identity as LCs that have migrated to the skin-draining LN (Fig. 1 C). Importantly, we did not observe EGFP expression in any other cell present in the LN. There were no detectable EGFP+ cells in spleen, mesenteric LN, and thymus (Fig. 2 A).
Thus, expression of the Cre transgene appears to be limited to epidermal LCs and to LCs that have migrated to the skin-draining LN, which is consistent with our prior experience using this BAC (12). It is important to note that endogenous mouse Langerin is expressed by several populations of CD8+ DCs that are present throughout the secondary lymphoid tissue. We and others have shown that these cells are not derived from the epidermis (12, 18, 19). These Langerin+, CD8+ DCs were present in Langerin-Cre mice in many tissues (Fig. 2 B). Although we are not sure why expression of Cre under the control of the human Langerin BAC locus is limited to epidermal LCs and not other mouse Langerin-expressing cells, it is clear that these other Langerin-positive cells do not express the transgene and will not confound the analysis of subsequent experiments.
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LCs require autocrine/paracrine TGFß1 for development
There are many potential sources of TGFß1 available to the developing LC in the skin, including keratinocytes, fibroblasts, resident T cells, and LCs themselves (9, 23). To examine whether autocrine secretion of TGFß1 participates in LC development, we bred Langerin-Cre mice to mice in which the gene for TGFß1 was floxed, thereby generating mice with a LC-selective ablation of TGFß1 (24). These Langerin-Cre TGFß1f/f mice appeared grossly normal, did not have overt histologic evidence of autoimmune disease in the skin, and had normal numbers of lymphocytes and DCs in their spleen and LN (unpublished data). We consistently observed a large decrease in the number of LCs in Langerin-Cre TGFß1f/f mice. LCs comprised 0.02–0.1% of epidermal cells in Langerin-Cre TGFß1f/f mice compared with 0.42–1.17% in littermate controls (Fig. 4, A and B).
Immunofluorescence of whole-mounted ear epidermis confirmed this result. In Langerin-Cre TGFß1f/f mice, LCs were absent from the vast majority of the ear, but could be observed focally as MHC-II+, Langerin+ cells in a few areas (Fig. 4 C). As was seen with the Langerin-Cre TGFßRIIf/f mice, escaped LCs were found in clusters that, interestingly, were often located at the edge of the ear.
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The requirement for LC-derived TGFß1 in LC development was unexpected, given the observation by Borkowski et al. that donor-derived LCs develop in TGFß1–/–
WT BM chimeric mice (11). One explanation for the apparent discrepancy between our results and theirs is that LC repopulation of the epidermis after BM transplantation may not be analogous to epidermal population during ontogeny and, in contrast to our results, could occur in the absence of LC-derived TGFß1. We examined this by creating BM chimeras using Langerin-Cre TGFß1f/f and control littermate Cre– TGFß1f/f mice (both CD45.2+) as BM donors and WT CD45.1 congenic B6 mice as recipients. Half of the recipients were treated with UVC 1 d after transplant, which eliminates host LCs and is known to enable the development of donor-derived LCs in the epidermis after BM transplantation (22). Hematopoietic engraftment in both sets of chimeras was confirmed by detecting CD45.2 by flow cytometry 8 wk after transplant (unpublished data). As expected, immunofluorescence of epidermal whole mounts revealed that UVC-treated recipients of control Cre– TGFß1f/f BM developed normal numbers of CD45.2+ (donor) Langerin+ LCs throughout the epidermis (Fig. 5 A).
In contrast, UVC-treated recipients of Langerin-Cre TGFß1f/f BM had virtually no detectable LCs, and the rare LCs present were of donor origin. Recipients of Langerin-Cre TGFß1f/f and control BM that were not irradiated with UVC retained LCs of recipient origin (Fig. 5 B), as expected (22). Thus, LC epidermal repopulation after BM transplantation recapitulated the steady state and, in our hands, is dependent on LC-derived TGFß1.
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The general importance of TGFß1 in LC development was already appreciated based on the absence of LCs in TGFß1–/– mice and the ability of TGFß1 to enhance production of LCs in in vitro cultures (6–8). The lack of LCs in Langerin-Cre TGFßRII mice demonstrates that TGFß1 acts directly on LCs and not indirectly via another cell type. This was a nontrivial possibility given the large number of cell types that express receptors for TGFß. In addition, because Langerin, and hence Cre, are thought to be expressed only by mature LCs, our data indicates that LCs must require TGFß1 after they begin to express Langerin (14). Indeed, Langerin mRNA transcripts are detectable in the skin of TGFß1–/– mice, and local introduction of TGFß1 can rescue LC development in TGFß1–/– mice (10, 25). Considering these results with our data, we conclude that LC precursors become TGFß1 dependent only once they are in the skin and begin to express Langerin. TGFß1 signaling induces the transcription factor Id2 (26). The absence of both LCs and splenic CD8+ DCs in Id2–/– mice raised the possibility that both cell types may share a common TGFß1-dependent precursor (26). The requirement for TGFß1 by LCs only once they are already in the skin, however, suggests that Id2 could be required only after they have become distinct lineages.
Our observation that Langerin-Cre TGFß1f/f mice have a greatly reduced number of LCs clearly demonstrates a nonredundant, in vivo requirement for paracrine or autocrine TGFß1 for the development of mature LCs. Whether TGFß1 acts transiently to foster LC development and/or is required as a survival factor is unclear. TGFß1 is produced by epidermal keratinocytes, making it plausible that LC-derived TGFß1 allows survival until LCs reach the epidermis, at which point keratinocytes could instead provide the necessary TGFß1. Hematopoietic stem cells (HSCs) were thought to use an autocrine/paracrine TGFß loop to maintain HSC quiescence (27). However, in vivo experiments, using conditionally ablated TGFßRII revealed that the absence of TGFß signaling had no effect on HSCs, and the reliance on TGFß in vitro was presumably caused by an indirect effect, such as the absence of soluble or environmental factors present in vivo (27). This highlights the difficulty of studying TGFß in vitro and the importance of in vivo experimental systems. We believe this is the first documented hematopoietic cell type that is dependent on TGFß for its development. Recent studies have also revealed an important function for T cell–derived TGFß1 in regulating T cell function (24). Thus, regulation via TGFß autocrine/paracrine loops may be a more common phenomenon than previously realized.
The deletion of the floxed loci in TGFßRIIf/f mice does not occur in every LC precursor, which allows some to retain sensitivity to TGFß1 and repopulate the empty epidermal niche. One explanation for this would be that rare LC precursors in Langerin-Cre mice express insufficient levels of Cre to delete both alleles of the floxed locus. This could explain why all LCs express EGFP in Langerin-Cre Rosa-EGFP mice, which only require deletion of a single floxed allele. Other floxed genes that are not required for LC survival, such as I-Aß, have both alleles efficiently excised by all LCs (unpublished data). Thus, it is more likely that the strong selective advantage of retaining sensitivity to TGFß1 allows what would otherwise be a very rare cell to expand. The observation that escaped LCs in Langerin-Cre TGFßRIIf/f occur in clusters argues that fully differentiated LCs derive from locally proliferating precursors in the steady state (4, 21, 22). Moreover, the expanding size of the clusters with age suggests that LCs are proliferating within the epidermis, though proliferation in the dermis and subsequent migration into the epidermis cannot be excluded.
Langerin-Cre TGFß1WT UV-treated chimeras do not develop donor-derived LCs. Thus, LC-derived TGFß1 is required for LC repopulation after UV treatment, as well as to establish a normal complement of epidermal LCs during ontogeny. The absence of LCs in Langerin-Cre TGFßF/F chimeras was particularly surprising, given the presence of donor-derived LCs in the original TGFß1–/–WT experiments by Borkowski et al. (11). A potentially important distinction is that in the Borkowski et al. experiments, all hematopoietic cells lacked the gene for TGFß1, unlike Langerin-Cre TGFß1 chimeras, in which the defect was limited to LCs. Levels of TGFß2 are elevated in the skin of TGF1ß–/– mice (11). It is possible that in the absence of hematopoietically derived TGFß1, compensatory TGFß2 or other TGFß family members such as activin, which potentially could promote LC development, were induced, and thus masked the physiologic requirement for LC-derived TGFß1 (10, 11, 28). It is also important to note that Borkowski et al. observed donor-derived LCs in control and TGFß1–/– chimeras in the absence of UV treatment. Others have clearly shown that LCs are radio resistant, and repopulation from donor BM requires ablation of host LCs, such as that which occurs after UV treatment or cutaneous graft versus host disease (22, 29), a finding that we have confirmed. Although no obvious evidence of cutaneous autoimmunity was observed in the Borkowski study (Udey, M., personal communication), minor histocompatability differences between a partially backcrossed donor and an inbred recipient could have accounted for the presence of donor LCs in the absence of UV treatment and allowed LC development in the absence of LC-derived TGFß1.
LC-derived TGFß1 could also participate in other aspects of LC biology, such as maintaining an immature LC phenotype, determining whether precursors become LCs or other DC subtypes (e.g., dermal DCs), and/or regulating cutaneous immune responses. Because LCs lacking TGFß1 fail to develop, it is much more challenging to examine the possible roles of TGFß1 in subsequent phases of the LC lifecycle. We are in the process of generating mice that will express an inducible form of Cre in LCs, which should permit us to investigate the ongoing roles of TGFß1 in LC biology beyond the required initial autocrine/paracrine loop we have defined in this work.
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MATERIALS AND METHODS |
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TopABSTRACTRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mice.
Langerin-Cre mice were bred onto the following strains: Rosa26.EFGP (The Jackson Laboratory), floxed TGFßRII (a gift from H. Moses, Vanderbilt University School of Medicine, Nashville, TN; reference [20]), floxed TGFß1 (24), and TGFß1-GFP (unpublished data). C57BL/6 CD45.1 mice were obtained from The Jackson Laboratory. All experiments were performed with age- and sex-matched mice. Mice were housed in microisolator cages and fed autoclaved food and acidified water. The Yale Institutional Animal Care and Use Committee approved all mouse protocols.
Antibodies.
Antibodies to the following targets were used: muLangerin (929F3; provided by S. Saeland, Dendritics, Dardilly, France), CD11c (N418-FITC and APC; eBioscience), I-A/E (M5/144.15.2-FITC and biotin; BioLegend), CD11b (M1/70-PE; BD PharMingen), CD45.1 (A20-FITC; BD PharMingen), CD45.2 (104-FITC; BD PharMingen), and CD8 (Ly-2-PE; BD PharMingen). NLDC-145 (anti-DEC-205) and 24G2 (anti-FcR
) were purified from hybridoma supernatants, as previously described (30). Conjugation to biotin or Alexa Fluor 647 was performed according to the manufacturer's directions (Invitrogen).
Flow cytometry.
Single-cell suspensions of epidermis, LN, thymus, and spleen were obtained and stained as previously described (12). Live/dead discrimination was obtained using propidium iodide (Invitrogen) or ethidium monoazide (Invitrogen). Samples were analyzed on a FACSCalibur or LSR-II flow cytometer (BD Biosciences).
Immunofluoresence.
Epidermal sheets were prepared by affixing ears to slides using double-sided adhesive (3M), followed by incubation in 21 mM EDTA in PBS for 2 h at 37° and physical removal of the dermis, as previously described (12).
Generation of chimeric mice.
BM cells were obtained from either Langerin-Cre TGFßf/f or Cre– littermate control mice. Cells were incubated in ACK buffer for erythroid cell lysis and resuspended in injection buffer (1 x PBS, 10 mM Hepes, 2.5% acid citrate dextrose anticoagulant, and 0.5% penicillin/streptomycin). Recipient B6 CD45.1 mice received 775 cGy from a cesium irradiator and were reconstituted with 107 cells/mouse. 1 d after transplantation, one cohort of mice was exposed to 450 mJ UVC light. Mice were rested for at least 8 wk before experimentation.
Statistics.
Statistical comparisons between groups were made using a standard two-tailed Student's t test. Linear regression was used to evaluate for correlation in Fig. 3 B.
Online supplemental material.
Fig. S1 shows the generation of Langerin-Cre BAC. Fig. S2 shows that escaped epidermal MHC-II+ cells in Langerin-Cre TGFßRIIf/f mice are LCs. The online version of this article is available at http://www.jem.org/cgi/content/full/jem.20071401/DC1.
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Acknowledgments |
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This work was supported by National Institutes of Health grants R01 HL66279 and R01 AR44077 (to M.J. Shlomchik) and K08 AR651092 (to D.H. Kaplan).
The authors have no conflicting financial interests.
Submitted: 10 July 2007
Accepted: 25 September 2007
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REFERENCES |
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TopABSTRACTRESULTS AND DISCUSSIONMATERIALS AND METHODSREFERENCES |
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