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The Journal of Immunology, 2001, 166: 7178-7182.
Copyright © 2001 by The American Association of Immunologists

In Vivo-Matured Langerhans Cells Continue to Take Up and Process Native Proteins Unlike In Vitro-Matured Counterparts

Christiane Ruedl1, Pascale Koebel and Klaus Karjalainen

Basel Institute for Immunology, Basel, Switzerland


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results and Discussion
 References
 
We have been able to identify the cell subset derived from Langerhans cells in the total dendritic cell population of the peripheral lymph node and hence to follow their trafficking under normal physiological conditions as well as upon skin irritation. As expected, the rapid mobilization of Langerhans cells triggered by inflammatory signals into the draining lymph node correlated with an up-regulation of costimulatory molecules and with an enhanced immunostimulatory capacity. Surprisingly, however, these cells, instead of shutting down, maintain the capacity to capture and process protein Ags during the couple of days they stay alive in stark contrast to in vitro-matured dendritic cells.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results and Discussion
 References
 
The behavior of Langerhans cells (LC)2 has become the paradigm of dendritic cell (DC) biology (1). In the skin, LC are actively sampling and processing invading exogenous Ags and upon inflammatory signals they start to migrate to the draining lymph node (LN) (2). During this transit, LC undergo a maturational process which leads to pronounced phenotypic changes characterized by enhanced T cell stimulatory activity (3, 4, 5).

DC maturation can be conventionally followed by in vitro cultures upon addition of inflammatory cytokines (6, 7). Not only do DCs up-regulate the costimulatory molecules B7-1 and B7-2 and CD40, but they also lose their capacity to capture and process protein Ags as well as to synthesize MHC class II molecules (8, 9). Furthermore, the efficiency of the formation of immunogenic MHC class II/peptide ligands is reduced in the lysosomal compartments (10) and, possibly due to down-regulation of endocytosis, the half-life of MHC class II complexes on the cell surface is increased up to 10-fold (11, 12). The end product of this maturation is a highly immunostimulatory DC that retains the "memory" of the original antigenic exposure.

It is generally assumed that these events take place also in vivo when, during a cutaneous inflammation, LC leave the skin and migrate to lymphoid organs for presentation of the MHC-peptide complexes to T lymphocytes. However, herein, we show that in vivo-matured LC that reached the LNs still are able to capture and process exogenous Ags even with increased efficiency as compared to that of normal resident DCs in the LNs, suggesting that the paradigm of maturation based on in vitro studies is not strictly followed in vivo.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results and Discussion
 References
 
Mice

BALB/c and C57BL/6 mice were provided by IFFA-Credo (Saint Germain-sur-l’Abresle, France). Transgenic mice expressing a MHC class II-restricted TCR specific for the OVA peptide323–339 (DO11.10) have been described previously (13). Mice were bred under specific pathogen-free conditions according to Swiss federal law.

Activation of LC in vivo

Green fluorescent Cell Tracker (50 µl; Molecular Probes, Leiden, The Netherlands), dissolved 1:20 in a 50:50 (v/v) acetone:dibutyl phtalate mixture, was painted on the dorsal site of the ears. To ensure full DC maturation in vivo, one mouse group was injected intradermally (i.d.) with LPS (LPS from Escherichia coli, 100 ng/mouse; Difco, Detroit, MI). One day later, draining LNs were collected and DCs were isolated as previously described (14). Briefly, LNs were digested twice for 30 min at 37°C in IMDM supplemented with 5% FCS with 100 µg/ml collagenase D (Boehringer Mannheim, Mannheim, Germany) in a shaking water bath. Cells were recovered, resuspended in a Optiprep-gradient (Nycomed, Norway), and centrifuged at 600 x g for 15 min. Low-density cells in the interface were harvested and incubated for 30 min on ice with PE-labeled anti-CD11c and Cy5-labeled anti-CD40. CD11chighCD40high cells were sorted with a FACStarPlus (Becton Dickinson, Mountain View, CA) or analyzed using a FACSCalibur (Becton Dickinson) excluding propidium iodide-positive dead cells.

Phenotype of in vitro- and in vivo-matured LC

To determine the phenotype of in vivo-matured LC, ears were painted with green fluorescent Cell Tracker with or without additional LPS injection as described above. DCs were isolated 1 day later from the draining LNs and stained for 30 min on ice with biotinylated anti-CD11c, Cy5-labeled anti-CD40, and PE-labeled anti-B7-1, anti-B7-2, and anti-MHC class II, respectively. Cells were washed and incubated for another 30 min with streptavidin-PerCP (Beckton Dickison). Cell Tracker+ and Cell Tracker- cells in the fraction CD11chighCD40high were analyzed for expression of both costimulatory molecules B7-1 and B7-2 and MHC class II (I-A, I-E) by FACS analysis. In vitro-matured DCs were obtained by incubating overnight the sorted CD11chighCD40high cells in the presence of 100 ng/ml LPS.

Isolation of LC after skin irritation

Acetone/dibutyl phtalate mixture was painted on the dorsal site of the ears and LPS was injected i.d. After 30 min, ear skin from BALB/c mice was split in dorsal and ventral halves, cut into small pieces, and digested twice for 30 min at 37°C in IMDM supplemented with 5% FCS with 100 µg/ml collagenase D. Released cells were collected, resuspended in an Optiprep gradient (Nycomed, Oslo, Norway), and centrifuged at 600 x g for 15 min. Low-density cells in the interface were harvested and labeled for 30 min on ice with PE-labeled anti-MHC class II.

Skin organ culture

Ear skin from BALB/c mice was split in dorsal and ventral halves and cultured in a 24-well plate (one ear per well) in the presence of 100 ng/ml LPS. Skin-derived DCs were obtained 1 or 2 days later by collecting the cells migrated from the skin explants into the culture medium and identified as MHC class II-expressing cells.

In vitro stimulation assays

For the in vitro T cell assays, LC obtained from the peripheral LNs (CD11chighCD40high fraction) were sorted on the basis of green fluorescence (Cell Tracker+ and Cell Tracker- fractions) using a FACStarPlus, as described above, obtaining a purity of >97%. For the MHC class II-restricted OVA presentation assay, 5 x 103 Cell Tracker+ and Cell Tracker- LCs obtained from treated mice and unstimulated LC were cocultured with 5 x 104 CD4+ OVA-specific T cells in the presence of different concentrations of OVA (10 µM to 100 nM). For comparison, 104 sorted CD11chighCD40high were in vitro cultured with cytosine-guanosine oligonucleotides (1 µM), LPS (100 ng/ml), GM-CSF (50 ng/ml) + TNF-{alpha} (50 ng/ml), or without any stimulus. After 24 h, stimuli were washed away and DCs were cocultured with 5 x 104 CD4+ OVA-specific T cells.

For the MLR, different numbers of sorted DC (H-2d, 2 x 103–1.25 x 102) were added to 1 x 105 purified allogeneic T cells obtained from spleen of C57BL/6 (H-2b) mice.

T cell proliferation was assessed by [3H]thymidine (1 µCi/well) uptake in a 16-h pulse after 4 days for the MLR and 2 days for MHC class II-restricted presentation assay.

Determination of fluid phase and receptor-mediated endocytosis

For Ag-pulsing experiments, an enriched LN DC population of Cell Tracker-treated mice (with or without i.d. LPS) and in vitro-activated CD11chighCD40high were incubated 1) for 30 min with 100 µg/ml Cy5-labeled OVA at 4°C and 37°C or 2) for various times (15, 30, and 60 min) with Cy5-labeled mannosylated-BSA and Cy5-labeled BSA at 4°C and 37°C. The cells were washed three times with cold PBS containing 1% BSA and stained with biotinylated anti-CD11c and PE-labeled anti-CD40 for 30 min on ice. After another 30 min with streptavidin-PerCP, four-color FACS analysis was performed.


   Results and Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results and Discussion
References
 
LC immigrated into the draining LNs upon skin irritation are fully mature and highly immunostimulatory

We have previously defined at least four distinct DC subpopulations in the peripheral LNs by different CD11c and CD40 expression patterns (staining profile is shown in Fig. 1GoA). One DC subset, the CD11chighCD40high cells, consists of immigrated LCs (iLC) from the epidermis, since only this fraction occasionally displays Birbeck granules, expresses E-cadherin, and carries epicutaneously applied cellular dye (15). This identification of progeny of skin LC in the peripheral LNs allowed us to study their functional behavior after migration and maturation processes in vivo.



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  		FIGURE 1. Skin irritation induced migration and maturation of LC. A, Dual-color CD11c/CD40 staining of auricular LN DCs 24 h after epicutaneous application of acetone/dibutyl phtalate. B, Gated CD11chighCD40high cells were analyzed for the presence of green fluorescent cells after Cell Tracker painting in the absence (upper histogram) or in presence of i.d. LPS injection (lower histogram). C, Expression analysis of B7-1, B7-2, and MHC class II on unstimulated, in vitro-stimulated, and in vivo-stimulated iLC in the LNs. Triple staining with PerCP-labeled CD11c, APC-labeled CD40, and PE-labeled B7-1, B7-2, and MHC class II, respectively. Values represent the median of fluorescence intensity.

 
To induce migration and maturation of LC in vivo, we applied epicutaneously a skin irritant consisting of acetone/dibutyl phtalate with or without i.d. injection of LPS. LPS was included to guarantee the strongest maturational signal for LC in vivo (15, 16). LC transport to LN was monitored by the addition of a green fluorescent cellular dye (Cell Tracker) in the skin irritant and LNs were removed ~24 h later that correspond to the massive, but transient peak of iLC (15). In the absence of concomitant LPS injection, Cell Tracker+ cells (~70%) were clearly detectable after 20 h in the LC-derived subset of CD11chighCD40high cells (Fig. 1GoB). Including LPS in the injection mixture reduced the percentage of Cell Tracker+ cells (30%). This is consistent with the fact that LPS not only triggers maturation, but also induces cell death in the DC compartment (16, 17) and, therefore, we feel assured that our LPS treatment had its desired effect.

To correlate the migration of LC with maturation in vivo, we analyzed the expression of MHC class II and of two different costimulatory molecules, B7-1 and B7-2, their up-regulation being the hallmark for DC maturation generally (18, 19, 20). Indeed both costimulatory molecules were up-regulated in iLC bearing the Cell Tracker dye, whereas Cell Tracker- iLC from the same LNs display similar expression levels as iLC obtained from LNs of untreated mice (Fig. 1GoC). The LPS injection induced only a small additional boost of expression of both costimulatory molecules when compared to Cell Tracker+ iLC obtained from mice treated only with the solvent. Intradermal injection of LPS also stimulated slightly the Cell Tracker- fraction, probably due to diffusion of some traces of LPS through the lymphatics into the draining LNs. MHC class II levels were comparably high on all iLC sets analyzed.

The enhancement of surface B7-1 and B7-2 expression on in vivo-migrated iLC led to substantially higher immunostimulatory ability. In fact, when cocultured with allogeneic T cells, the Cell Tracker+ fraction was clearly more immunogenic than the unstimulated Cell Tracker- iLC fraction obtained from LNs of treated or untreated mice (Fig. 2Go). Again, matured iLC obtained from LPS-treated mice were slightly more immunostimulatory than matured iLC obtained from mice painted with the solvent containing Cell Tracker only.



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  		FIGURE 2. Comparison of Cell Tracker+ and Cell Tracker- CD11chighCD40high DCs for their immunostimulatory capacity in MLR. Mice were treated epicutaneously with Cell Tracker, with or without i.d. LPS injections. DCs were prepared from the draining LNs, stained for CD11c/CD40, and sorted on the basis of CD11chighCD40high expression and green fluorescence (Cell Tracker+) or correspondent negative fraction (Cell Tracker-). Different numbers of sorted DCs (2 x 103–1.25 x 102) were added to 2 x 105 purified allogeneic T cells obtained from spleens of C57BL/6 mice. T cell proliferation was assessed by [3H]thymidine (1 µCi/well) uptake in a 16-h pulse after 4 days. The data shown are the mean ± SD of triplicate wells. One representative experiment of three is shown.

 
Taken together, the observed phenotypical and functional changes clearly indicate that our approach to induce in vivo maturation results in cells having characteristics of fully activated DCs.

In vivo-, but not in vitro-matured LC efficiently present soluble protein to Ag-specific T cells

Based on the observation that LC undergo a maturation process during the transition from the skin into the LNs, we monitored the capacity of matured iLC to take up and present soluble proteins, such as OVA, to Ag-specific T cells. Experiments in vitro have clearly demonstrated that DC maturation abolishes the ability to endocytose native proteins (21, 22) and concomitantly increases the stability of MHC class II complexes formed on their cell surface prior to maturation (11). Consistently, also in our hands, in vitro-matured LC were unable to present OVA to Ag-specific T cells (Fig. 3GoA). However, to our surprise, this was not the case when the maturation occurred in vivo. When Cell Tracker+ and Cell Tracker- cells (i.e., matured and naive, respectively) were purified from draining LNs 24 h after skin irritation, pulsed with OVA, and then cocultured with Ag-specific CD4+ T cells, both fractions were capable of stimulating Ag-specific proliferation. Furthermore, as shown in Fig. 3GoB, immigrated Cell Tracker+ iLC were even more efficient in presenting OVA to Ag-specific CD4+ T cells when compared to the Cell Tracker- iLC or iLC obtained from LNs of untreated mice. As a note, contaminating peptides in our OVA preparation can not explain the above result, because OVA peptide is presented equally well by in vitro- and in vivo-matured DC (data not shown).



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  		FIGURE 3. In vivo-matured LC can efficiently present native proteins unlike the in vitro-matured counterparts. A, In vitro-applied maturation stimuli (CpGs, LPS, and GM-CSF + TNF-{alpha}) abolish the ability of DCs to present native OVA to Ag-specific CD4+ T cells. The CD11chighCD40high fraction of LN DCs was sorted and in vitro stimulated as described in Materials and Methods. One day after, 104 DCs were cocultured with 5 x 104 OVA-specific T cells in the presence of native OVA (10–0.1 µM). B, Cell Tracker+ DCs were most efficient in presenting native protein to Ag-specific CD4+ T cells. Cell Tracker- and Cell Tracker+ fractions were purified as described in the legend to Fig. 2Go. DCs (5 x 103) were cocultured with 5 x 104 OVA-specific T cells in the presence of different OVA concentrations (10–0.1 µM). T cell proliferation was assessed by [3H]thymidine (1 µCi/well) uptake in a 16-h pulse after 2 days. The data shown are the mean and SD of triplicate wells. One representative experiment of three is shown.

 
Fluid phase and receptor-mediated endocytosis is maintained after in vivo maturation of LC

To further elucidate the potential mechanistic differences between in vivo- and in vitro-matured LC, these cells were pulsed with Cy5-labeled OVA. As reported previously and also confirmed herein, in vitro matured LC were unable to actively take up OVA at 37°C (Fig. 4GoA). Remarkably, in vivo-matured LC behaved differently. They had not shut down their capacity to endocytose, but showed an even increased capacity compared to that of normal resident DCs (Fig. 4GoA). Interestingly, as shown in Fig. 4GoB, in vivo-matured iLC were also more potent in receptor-mediated Ag uptake when compared to unstimulated normal DC, as shown by the uptake of mannosylated BSA. This was most likely due to a higher expression of a biological active mannose receptor, since DC pulsed with Cy-5-labeled mannosylated BSA at 4°C revealed about three times more cell surface binding to matured vs immature iLC (median of fluorescence of 640 vs 196). In contrast, in vitro-stimulated DCs were incapable of taking up not only BSA, but also mannosylated BSA (Fig. 4GoB).



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  		FIGURE 4. Fluid phase and receptor-mediated endocytosis is not down-regulated in in vivo-matured LC. In vivo- and in vitro-matured CD11chighCD40high (day 1) were monitored for fluid phase and receptor-mediated endocytosis, respectively. Cells were incubated at 37°C or 4°C for 30 min with 100 µg/ml Cy5-labeled OVA (A) and with 100 µg/ml Cy5-labeled BSA (left) or 100 µg/ml Cy5-labeled mannosylated BSA (right), respectively, for 15, 30, and 60 min (B). The cells were washed with cold 1% BSA/PBS three times, stained as described in Materials and Methods, and analyzed by FACS. The median of fluorescence is shown. The background fluorescence obtained at 4°C was subtracted. A, {square} Cell Tracker- cells; {blacksquare}, Cell Tracker+ cells. B, {square}, Cell Tracker- cells; {blacksquare}, Cell Tracker+ cells; • in vitro-matured iLC.

 
To exclude the possibility that we "outgated" the further matured DC, we analyzed all newly immigrated Cell Tracker+ cells in the draining LNs regardless of their CD11c/CD40 expression pattern during the 3-day period when they were still detectable in the LNs (Fig. 5GoA). During this time they maintained their phenotype of mature DCs (Fig. 5GoB) and the capacity to endocytose at levels higher or comparable to that of resident normal DCs (Fig. 5GoC).



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  		FIGURE 5. A, Detection of green fluorescent cells in draining LNs upon cutaneous application of Cell Tracker. The enriched population of DCs was stained with APC-labeled CD11c and positive cells were monitored over a period of 3 days for the presence of green fluorescent cells (filled histograms). B, B7-2 levels on Cell Tracker+ and Cell Tracker- cells obtained from draining LNs after 1, 2, and 3 days upon skin irritation. C, Cell Tracker+ and Cell Tracker- fractions of total CD11c+ DC (days 1–3) were analyzed for uptake of mannosylated BSA. Cells were incubated with 50 µg/ml Cy5-labeled mannosylated BSA for 30 min at 37°C, washed, stained as described in Materials and Methods, and analyzed by FACS. Values represent the median of fluorescence intensity. {square}, Cell Tracker- cells; {blacksquare}, Cell Tracker+ cells.

 
To complete our analysis, we measured the ability of freshly isolated LC from the skin to endocytose (Fig. 6Go). It is clear that LC in situ are the most active in this process. However, when placed in vitro, these cells abruptly lose the capacity to endocytose, whereas in vivo this capacity goes gradually down, but is never abolished.



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  		FIGURE 6. Differences in Ag uptake between in vitro- and in vivo-matured LC. Freshly isolated LC, referred as day 0, were isolated directly from the skin by enzymatic digestion. In vivo-matured LC were isolated from the draining LNs at days 1 and 2 upon skin irritation and i.d. LPS injection. In vitro LC were generated in skin organ cultures and stimulated for 1 and 2 days with LPS. Freshly isolated, in vivo-matured, and in vitro-matured LC were pulsed with 100 µg/ml Cy5-labeled BSA for 30 min, washed twice with cold 1% BSA/PBS, and stained with CD11c (for LN LC) and MHC class II (for skin-derived LC). The median of fluorescence is shown.

 
Our results modified the paradigm of DC behavior. In fact, we show here that in vivo-matured skin-derived DCs obtained from the LNs continue to take up and present native Ag. In agreement with our data, Weinlich et al. (5) recently reported that populations of migrating LC in skin organ cultures up-regulate markers of maturity, but partially retain the capacity to process native protein Ags. In addition, it has been shown that, upon application of contact sensitizers, LC obtained from epidermis display a clear mature phenotype, but retain their Ag-presenting functions for native proteins (22). Interestingly, Liu and MacPherson (23) obtained similar results some years ago when they analyzed the Ag-processing ability of lymph-borne DCs collected from the thoracic duct of mesenteric lymphadectomized rats. They observed that DCs released from the intestine are, on one hand, functionally mature, but, on the other hand, also efficient in processing and presenting native protein Ags (23). It is then clear that activated LC do not lose their Ag uptake before they embark to the draining LNs, but rather they keep it up not only during their trip but also in the LNs for the most of the short time (~3 days) they survive there.

Concluding remarks

Maturing LC are not the only travelers in transit from the skin to the draining LNs, but also antigenic material thereof use the same lymphatics. Hence, it would make teleological sense that DCs, in transit and in final destination, while actually swimming in antigenic lymph, would not stop the uptake and processing of Ags, but would continue to do so and thereby to become "super" APCs ready to encounter T cells.


   Acknowledgments
 
We thank Marina Cella and Jean Pieters (Basel Institute for Immunology) for critical reading and comments on this manuscript and Tracy Hayden and Hubertus Kohler for their expertise and help in cell sorting. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche (Basel, Switzerland).


   Footnotes
 
1 Address correspondence and reprint requests to Dr. Christiane Ruedl at the current address, Cytos Biotechnology AG, Wagisstrasse 21, CH-8952 Zurich, Switzerland. E-mail address: Ruedl{at}cytos.com Back

2 Abbreviations used in this paper: LC, Langerhans cell; DC, dendritic cell; iLC, immigrated Langerhans cell; LN, lymph node; i.d., intradermal. Back

Received for publication September 12, 2000. Accepted for publication April 9, 2001.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results and Discussion
 References
 

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M. Menges, T. Baumeister, S. Rossner, P. Stoitzner, N. Romani, A. Gessner, and M. B. Lutz
IL-4 supports the generation of a dendritic cell subset from murine bone marrow with altered endocytosis capacity
J. Leukoc. Biol., April 1, 2005; 77(4): 535 - 543.
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N. S. Wilson, D. El-Sukkari, and J. A. Villadangos
Dendritic cells constitutively present self antigens in their immature state in vivo and regulate antigen presentation by controlling the rates of MHC class II synthesis and endocytosis
Blood, March 15, 2004; 103(6): 2187 - 2195.
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P. Saint-Mezard, C. Chavagnac, S. Bosset, M. Ionescu, E. Peyron, D. Kaiserlian, J.-F. Nicolas, and F. Berard
Psychological Stress Exerts an Adjuvant Effect on Skin Dendritic Cell Functions In Vivo
J. Immunol., October 15, 2003; 171(8): 4073 - 4080.
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N. S. Wilson, D. El-Sukkari, G. T. Belz, C. M. Smith, R. J. Steptoe, W. R. Heath, K. Shortman, and J. A. Villadangos
Most lymphoid organ dendritic cell types are phenotypically and functionally immature
Blood, September 15, 2003; 102(6): 2187 - 2194.
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F. Geissmann, M.C. Dieu-Nosjean, C. Dezutter, J. Valladeau, S. Kayal, M. Leborgne, N. Brousse, S. Saeland, and J. Davoust
Accumulation of Immature Langerhans Cells in Human Lymph Nodes Draining Chronically Inflamed Skin
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