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The Journal of Immunology, 2008, 181, 3745 -3749
Copyright © 2008 by The American Association of Immunologists, Inc.
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Cutting Edge: Instructive Role of Peripheral Tissue Cells in the Imprinting of T Cell Homing Receptor Patterns1

Fanny Edele*,{dagger}, Rosalie Molenaar{ddagger}, Dominique Gütle§, Jan C. Dudda, Thilo Jakob*, Bernhard Homey||, Reina Mebius{ddagger}, Mathias Hornef§ and Stefan F. Martin2,*

* Allergy Research Group, Department of Dermatology, University Medical Center, and {dagger} Faculty of Biology, University of Freiburg, Freiburg, Germany; {ddagger} Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands; § Department of Medical Microbiology and Hospital Hygiene, Medizinische Hochschule Hannover, Hannover, Germany; Benaroya Research Institute, Seattle, WA 98101; and || Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Tissue-specific homing of effector and memory T cells to skin and small intestine requires the imprinting of specific combinations of adhesion molecules and chemokine receptors by dendritic cells in the draining lymph nodes. In this study, we demonstrate that CD8+ T cells activated by Ag-pulsed bone marrow-derived dendritic cells were induced to express the small intestine homing receptors {alpha}4β7 integrin and chemokine receptor CCR9 in coculture with small intestinal epithelial cells. In contrast, in coculture with dermal fibroblasts the skin-homing receptor E-selectin ligand was induced. Interestingly, the imprinting of gut homing receptors on anti-CD3/anti-CD28 stimulated T cells was induced by soluble factors produced by small intestinal epithelial cells. Retinoic acid was identified as a crucial factor. These findings show that peripheral tissue cells directly produce homing receptor imprinting factors and suggest that dendritic cells can acquire their imprinting potential already in the peripheral tissue of origin.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Upon activation by dendritic cells (DC)3 in skin-draining lymph nodes, T cells up-regulate the skin-homing receptors E- (E-lig) and P-selectin ligands as well as the chemokine receptors CCR4 and CCR10 (1, 2, 3, 4, 5, 6). Activation by DC from mesenteric lymph nodes (MLN) and Peyer’s patches (PP) induces the small intestine homing receptors {alpha}4β7 integrin and CCR9 (4, 5, 6, 7, 8, 9). The role of lymph node-resident DC vs DC that immigrated from peripheral tissues has not yet been addressed. DC from MLN and PP express retinal dehydrogenases (RALDH). They produce the vitamin A metabolite retinoic acid (RA) that induces up-regulation of {alpha}4β7 and CCR9 (10). Lamina propria-derived CD103+ DC are responsible for the imprinting of gut homing receptors on T cells in PP and MLN (11, 12). Epidermal Langerhans cells were most efficient in the induction of skin-homing receptors on CD8+ T cells in vitro as compared with DC from skin-draining lymph nodes (4, 6). These findings suggest that the DC immigrating into draining lymph nodes from peripheral tissues, rather than the lymph node resident DC, are responsible for homing receptor imprinting. In support of this view, two independent homing phenotypes can be induced on T cells in the same lymph node by DC that immigrated from different peripheral sites (13). Moreover, the majority of DC in skin draining lymph nodes consists of immigrants, i.e., Langerhans cells and dermal DC (14).

For this work, we have studied the role of the peripheral tissue microenvironment in the imprinting of skin and small intestine homing receptors by DC in coculture systems. CD8+ P14 T cells (15, 16), upon activation with Ag-pulsed bone marrow-derived DC (BM-DC), up-regulated the skin-homing receptor E-lig in coculture with dermal fibroblasts or the gut homing receptors CCR9 and {alpha}4β7 in coculture with small intestinal epithelial cells (SIEC). Soluble factors such as RA induced the imprinting of the gut homing phenotype, whereas cell-cell contact with dermal fibroblasts was important for the induction of E-lig on T cells. Our findings suggest that peripheral tissue stromal and epithelial cells produce factors that can directly induce homing receptors on T cells. These factors may license DC to also produce such factors and/or allow for the DC to shuttle these imprinting factors to the naive T cells in the regional draining lymph nodes.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Mice

C57BL/6 and TCR-transgenic Thy1.1 congenic P14 mice (15, 16) were provided by the breeding facility of the University Medical Center Freiburg (Freiburg, Germany). All of the experimental procedures were in accordance with institutional, state, and federal guidelines on animal welfare.

Media and chemicals

BM-DC, P14 cells, and dermal fibroblasts were cultured in RP-10 (4). Small intestinal epithelial cells (m-ICc12) were cultured in m-IC medium as described (17).

The lymphocytic choriomeningitis virus peptide GP33 (KAVYNFATM) was from Hermann GbR. All-trans RA was from Sigma-Aldrich. 9-cis-RA and RA receptor (RAR) antagonists (RAR and the retinoid X receptor antagonist RXR26, respectively) were provided by B. Homey (Heinrich-Heine University, Dusseldorf, Germany).

Ab and flow cytometry

All Ab were from BD Biosciences unless stated otherwise and used as FITC, PE, or biotin conjugates. Biotin-conjugated Ab were revealed with streptavidin-PE-Cy5. The Ab used are the following: anti-CD16/CD32 (Fc{gamma}R II/III) (clone 2.4G2); anti-CD90 (Thy1.1) (clone HIS51); anti-CD8{alpha} (clone 53-6.7); anti-IAb (clone AF6-120.1); anti-CD11c (clone HL3); anti-CD103 (clone M290); anti-{alpha}4β7 (DATK32); E-selectin/human IgG-Fc-chimera (R&D Systems); anti-human-IgG-FITC (DakoCytomation); rat anti-CCR9 (18) provided by R. Förster (Medizinische Hochschule Hannover, Hannover, Germany); mouse anti-rat IgG (H+L) (Jackson ImmunoResearch Laboratories). FACS staining was done as described (4, 6). Data were acquired and analyzed on a FACScan instrument using BD CellQuest Pro software (BD Biosciences). Anti-pan TGF-β was purchased from R&D Systems.

Isolation and preparation of cells

BM-DC were prepared as described (4) but without IL-4. m-ICcl2 cells were differentiated for 6 days on collagen in 24-well plates and cultured as described previously (17). Primary SIEC were isolated as described (19). Dermal fibroblasts were isolated from the skin of 2-day-old mice with 5 U/ml dispase (Invitrogen) for 1 h at 37°C. The dermis was separated from the epidermis, washed in PBS, and incubated in collagenase I (500 U/ml) (Worthington Biochemical) for 45 min at 37°C. Cells were singularized, washed in PBS, and resuspended in medium. Medium was changed after 24 h and cells were cultured until confluent. P14 spleen cells were prepared as described (4, 6). Total splenocytes were used (referred to as P14 cells). CD8{alpha} (clone Ly-2) MicroBead (Miltenyi Biotec)-purified CD8+ P14 T cells were used in some experiments to exclude bystander cell effects.

In vitro priming of T cells

BM-DC were harvested on days 7–9 and pulsed with 1 µM GP33 peptide (BM-DC-GP33) (4, 6) or used unpulsed. BM-DC-GP33 (1 x 105/well) were incubated with P14 splenocytes (2 x 105/well) with or without m-ICc12 in 24-well plates (Greiner Bio One) for 4 days in a volume of 2 ml of RP-10/ m-ICc12 medium (1:1; v/v). RAR antagonists (8 µM RAR or 3 µM RXR) were added to these cocultures from the beginning. Cocultures using BM-DC-GP33 (1 x 104/well) were incubated with 2 x 104 splenocytes and 1 x 104 dermal fibroblasts in round-bottom, 96-well plates (Corning Life Science) for 6 days in a total volume of 200 µl of RP-10. Supernatants were collected at day 4 of coculture and stored at –2°C. Cells were analyzed by flow cytometry. Cell culture inserts (1 µm pore diameter; BD Falcon) were used in Transwell experiments. m-ICc12 or dermal fibroblasts were cultured at the bottom of 24-well plates, andDC-GP33 and P14 splenocytes were cocultured in the cell culture inserts. Cell numbers were as described above.

Ab activated splenocytes (soluble anti-CD3{epsilon} (clone 145-2C11; 3 µg/ml) and anti-CD28 (clone 37.51; 1.5 µg/ml)) (BD Biosciences) were primed by the addition of all-trans or 9-cis-RA (10 nM and 7.5 µM, respectively).

Isolation of RNA and real-time PCR

Total RNA was isolated from BM-DC, m-ICc12, and BM-DC cocultured with m-ICc12 for 4 days using RNeasy Mini Kit 50 (Qiagen). DC were reisolated with CD11c MicroBeads using an autoMACS following the manufacturer’s instructions or had been separated from m-ICc12 by Transwell culture inserts. cDNA was prepared from 1 µg of template RNA using Qiagen Omniscript reverse transcription kit (Qiagen). RALDH-1-, RALDH-2-, and RALDH-3-specific primers and primers for the housekeeping gene 18S RNA were designed using the Roche Universal Probe Library and were purchased from the TIB MOLBIOL Synthesis Laboratory. The corresponding probes were obtained by Molecular Biochemicals. Real-time PCR was performed on a LightCycler 1.5 (Roche Molecular Biochemicals) using the LightCycler TaqMan Master kit (Roche Molecular Biochemicals). The reaction mixture had a total volume of 20 µl and contained 1 µl of cDNA, 4 µl of Master Mix (TaqMan Master), 1 µl of each primer (forward and reverse, end concentration 0.33 µM, respectively), 1 µl of probe in a final concentration of 0.1 µM, and 12 µl of RNase free water. A negative control was always included and consisted of the same ingredients without any cDNA. The expression of transcripts was related to 18S RNA. Cycle threshold (CT) values for 18S were subtracted from CT values of RALDH 1, 2 and 3, respectively ({Delta}CT) and normalized to values to {Delta}CT of DC alone ({Delta}{Delta}CT). Fold increase was calculated by 2–({Delta}{Delta}CT).

Statistics and statistical analysis

Statistical analysis was conducted using Student’s t test or ANOVA (nonparametric) for the PCR data. Differences were statistically significant at p < 0.05.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Small intestinal epithelial cells induce {alpha}4β7 and CCR9 in T cell-BM-DC cocultures by soluble factors

It is conceivable that the Ag-loaded DC immigrating from peripheral tissues confer the information about their tissue of origin to T cells in local draining lymph nodes.

To analyze the role of the peripheral tissue microenvironment in homing receptor imprinting, TCR-transgenic P14 splenocytes (P14 cells), used as a source for GP33 specific CD8+ T cells, were cocultured with BM-DC-GP33 in the presence or absence of the SIEC line m-ICC12. Cells were analyzed by flow cytometry on day 4 of coculture (Fig. 1A). Almost all CD8+ T cells expressed both {alpha}4β7 integrin and CCR9 in the presence of m-ICc12 when compared with controls. A role for soluble factors was shown in Transwell experiments separating cocultures of P14 splenocytes and BM-DC-GP33 from m-ICc12 cells. The extent of homing receptor up-regulation was comparable to that in the cultures without Transwells (Fig. 1A, left column). E-lig was not detected (Fig. 1A, right column). Similar results were obtained with freshly isolated primary SIEC (Fig. 1B) or when using purified CD8+ P14 T cells instead of splenocytes (data not shown).


Figure 1
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  		FIGURE 1. Induction of {alpha}4β7 and CCR9 on DC-activated CD8+ T cells in the presence of small intestinal epithelial cells. A, P14 splenocytes were cultured for 4 days alone (top row), cocultured with BM-DC-GP33 (second row from top), cocultured with BM-DC-GP33 and SIEC (m-ICc12 (m-IC)) (third row from top), or cocultured with BM-DC-GP33 and separated from m-ICc12 by using Transwell culture inserts (bottom row). Homing receptor induction on P14 cells was measured by flow cytometry. One representative of five independent experiments is shown. Gating was on live Thy1.1+ cells. B, Similar results were obtained with freshly isolated SIEC. Data are representative for three independent experiments. Gating was on live Thy1.1+ cells. C, Supernatants from DC, P14 splenocytes, m-ICc12 (mIC), or freshly isolated SIEC (co)cultures were added as CM to P14 cells activated with anti-CD3{epsilon} and anti-CD28. Live Thy1.1+ cells were analyzed by FACS. Double-positive cells ({alpha}4β7/CCR9) were normalized to double-positive splenocytes cultured without supernatants. Data represents the mean of three independent experiments. *, p < 0.05, significant difference to CM from P14 cultures. MFI, Mean fluorescence intensity; n.d., not detected; TW, Transwell.

 
Supernatants from cocultures were used as conditioned medium (CM). P14 cells activated by anti-CD3{epsilon} and anti-CD28 and incubated with CM from cocultures that contained either m-ICc12 or primary SIEC significantly up-regulated {alpha}4β7 integrin and CCR9 compared with CM from P14 cells only (Fig. 1C). Interestingly, even CM from m-ICc12 cells alone and, to a lesser extent, from primary SIEC alone were able to induce gut homing receptor expression on CD8+ T cells (Fig. 1C).

These findings indicate that SIEC release soluble factors that can induce small intestine homing receptors on T cells. It remains to be determined whether the difference between primary SIEC alone and SIEC plus DC (Fig. 1C) is indicative of an imprinting of DC by SIEC.

Retinoic acid is involved in homing receptor imprinting in SIEC cocultures

Both isoforms of the vitamin A metabolite RA, all-trans and 9-cis-RA, efficiently induced {alpha}4β7 integrin and CCR9 on P14 T cells activated with anti-CD3 and anti-CD28 (data not shown) as previously reported (10). All-trans RA binds to RAR only, whereas 9-cis-RA binds to RAR and RXR. Both receptors mainly function as heterodimeric, ligand-inducible transcription factors (20).

To test a potential role of RA, mICc12 were cocultured with P14 cells and BM-DC-GP33 in the presence or absence of RAR antagonists. The up-regulation of CCR9 was completely blocked in the cocultures by both RAR and RXR antagonists whereas the expression level of {alpha}4β7 was only reduced (Fig. 2A). In contrast to the antagonists used in this study, the inhibition of RALDH by citral or that of RAR by the antagonist LE135 efficiently suppresses RA- or MLN-DC-induced {alpha}4β7 up-regulation (10). It has been reported that TGF-β is a potent regulator of {alpha}4β7 (21). Neutralization of TGF-β in the presence or absence of RAR and RXR antagonists had no effect on the expression of {alpha}4β7 in our cocultures (supplementary Fig. S1).4


Figure 2
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  		FIGURE 2. Effects of RA-receptor antagonists on the expression of gut homing receptors and induction of a gut-associated phenotype of DC by m-ICc12. A, P14 splenocytes were cocultured with BM-DC-GP33 and m-ICc12 (m-IC) in the absence (top) or presence of the RAR antagonist (middle) or the RXR antagonist (bottom). Gating was on live Thy1.1+ cells. MFI, Mean fluorescence intensity. B, Total RNA was isolated on day 4 of culture from BM-DC, mICc12 (mIC), BM-DC from Transwell (TW) cultures with m-ICc12, and BM-DC previously cocultured with m-ICc12 and reisolated using CD11c MACS separation. cDNA was prepared and real time PCR for RALDH1, RALDH2, and RALDH3 and the housekeeping gene18S was performed in triplicates. n.d., Not detected. C, Expression of CD103 on DC after coculture with m-ICc12. BM-DC were cultured in presence (shaded area) or absence of m-ICc12 (bold line), harvested, and stained at day 4. Cells were gated on CD11c/IAb double-positive cells. Histogram is representative of four independent experiments. Numbers indicate the mean fluorescence intensity.

 
These results suggest that SIEC play an important role in the induction of gut homing receptors on T cells by the production of imprinting factors such as RA. RA production by human intestinal epithelium has been reported (22) and seems to be crucial for gut homing receptor induction.

BM-DC show a gut-associated phenotype after coculture with m-ICc12

CD103+ DC isolated from MLN were the most potent in inducing a gut-homing phenotype on T cells compared with CD103– MLN DC (11, 12). They express RALDH and can produce the imprinting factor RA (10). Furthermore, almost all lamina propria DC, but only a subpopulation of DC from MLN, express CD103 ({alpha}E chain of the integrin {alpha}Eβ7). These CD103+ lamina propria DC produce RA (23). To evaluate whether BM-DC adopt a gut DC phenotype in the presence of SIEC in vitro, BM-DC were stained for CD11c, I-Ab, and CD103 before and after coculture with m-ICc12. At day 4 of coculture, only a slight but reproducible up-regulation of CD103 could be detected compared with BM-DC cultured alone (Fig. 2C). We also observed the induction of RALDH1 in DC after coculture with mICc12 (Fig. 2B). These data show a bias toward a gut-associated phenotype of the BM-DC induced by SIEC. This implies that DC may acquire the ability to produce RA in the tissue microenvironment of the lamina propria. Positive feedback loops for the production of RA have been defined (24, 25). Thus, interactions of DC with peripheral tissue cells may induce a differentiation program resulting in the tissue-specific phenotype of the DC (4, 5, 6, 7, 8, 9). It is also possible that DC shuttle soluble factors produced by peripheral tissue cells, in this case SIEC, to the lymph nodes as suggested for RA (22).

BM-DC induce E-selectin ligands in the presence of dermal fibroblasts

To test whether dermal fibroblasts from mouse skin have a similar impact on the imprinting of skin-homing receptors on T cells, cocultures with dermal fibroblasts, BM-DC-GP33, and P14 cells were set up and analyzed after 6 days. The skin-homing receptor E-lig was induced in these cocultures, in contrast to cultures without dermal fibroblasts (Fig. 3 left column). Induction of skin-homing receptors was not observed when cell culture inserts were used to separate DC and P14 cells from the fibroblasts (Fig. 3, left bottom panel). These results suggest that cell-cell contact is necessary for the induction of skin-homing receptors on T cells, although IL-12 can induce E-lig in vitro (26). Most likely this cell interaction takes place between DC and skin cells, as naive T cells do not have access to dermal fibroblasts before they are primed for skin homing in the lymph node in vivo. We did not see any effects on E-lig expression by the vitamin D3 metabolite calcitriol (data not shown), which helps to induce CCR10 expression on human T cells (27). CCR4 was up-regulated in an activation-dependent manner (data not shown) (4). Similar results were obtained in all of these settings when purified CD8 T cells were used instead of splenocytes, excluding the bystander effects of non-T cells. Expression of the gut homing receptors {alpha}4β7 integrin or CCR9 were not observed in these experiments (Fig. 3, right column).


Figure 3
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  		FIGURE 3. Induction of E-selectin ligand on DC-activated CD8+ T cells in the presence of dermal fibroblasts. Expression levels of E-lig, {alpha}4β7, and CCR9 on P14 cells cultured with BM-DC-GP33 in the absence (top row) or presence of dermal fibroblasts (middle row). Dermal fibroblasts were separated from splenocytes cocultured with BM-DC-GP33 by Transwell culture inserts (TW; bottom row). All plots are representative for three experiments. Gating was on live Thy1.1+ cells.

 
Our findings demonstrate an instructive role for peripheral tissue cells in the imprinting of skin and small intestine homing receptors on T cells. It has been reported that stromal cells can influence DC differentiation (28, 29, 30) (reviewed in Ref. 31). For Langerhans cells that differentiate in the skin from monocyte precursors (32, 33), a role for both contact-dependent mechanisms and soluble factors in the acquisition of tissue-specific characteristics has been described (34, 35). In summary, we suggest that the peripheral tissue microenvironment conditions DC to shuttle topographical information to the lymph node in a bimodal fashion. As reported, DC may themselves be induced to produce factors for homing receptor imprinting (10) and, in addition, may transport factors produced by peripheral tissue cells to the draining lymph nodes. This would license the DC to induce tissue-specific homing receptors and thereby pass the information about their tissue of origin and the site of Ag entry on to the T cells.


   Acknowledgments
 
We are grateful to Dr. Alain Vandewalle, INSERM U773, Paris, France, for providing the m-ICl2 cell line and to Cindy Reinhold for technical assistance.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
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 Deutsche Forschungsgemeinschaft Grants MA1567/8-1 (to S.F.M.) and HO2236/5-2 (to M.H.), Swedish Research Council Grant K2003-31P-14792 (to M.H.), and Thyssen Foundation Grant AZ 10.05.2.173 (to M.H.). Back

2 Address correspondence and reprint requests to Dr. Stefan F. Martin, Allergy Research Group, Department of Dermatology, University Medical Center Freiburg, Hauptstrasse 7, D-79104 Freiburg, Germany. E-mail address: stefan.martin{at}uniklinik-freiburg.de Back

3 Abbreviations used in this paper: DC, dendritic cell; BM-DC, bone marrow-derived DC; CM, conditioned medium; CT, cycle threshold; E-lig, E-selectin ligand; MLN, mesenteric lymph nodes; PP, Peyer’s patch; RA, retinoic acid; RALDH, retinal dehydrogenase; RAR, RA receptor; RXR, retinoid X receptor; SIEC, small intestinal epithelial cell. Back

4 The online version of this article contains supplemental material. Back

Received for publication January 30, 2008. Accepted for publication July 11, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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