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The Journal of Immunology, 2006, 176: 1311-1315.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Identification of E-Cadherin as a Ligand for the Murine Killer Cell Lectin-Like Receptor G11

Carsten Gründemann*, Monika Bauer{dagger}, Oliver Schweier*, Nanette von Oppen*, Ute Lässing{dagger}, Philippe Saudan{dagger}, Karl-Friedrich Becker{ddagger}, Klaus Karp§, Thomas Hanke2,§, Martin F. Bachmann{dagger} and Hanspeter Pircher3,*

* Department of Immunology, Institute of Medical Microbiology and Hygiene, University of Freiburg, Freiburg, Germany; {dagger} Cytos Biotechnology AG, Schlieren-Zurich, Zurich, Switzerland; {ddagger} Institute of Pathology, Technical University, Munich, Germany; and § Institute for Virology and Immunobiology, University of Wurzburg, Wurzburg, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and by T cells. In both humans and mice, KLRG1 identifies Ag-experienced T cells that are impaired in their proliferative capacity but are capable of performing effector functions. In this study, we identified E-cadherin as a ligand for murine KLRG1 by using fluorescently labeled, soluble tetrameric complexes of the extracellular domain of the murine KLRG1 molecule as staining reagents in expression cloning. Ectopic expression of E-cadherin in B16.BL6 target cells did not affect cell-mediated lysis by lymphokine-activated NK cells and by CD8 T cells but inhibited Ag-induced proliferation and induction of cytolytic activity of CD8 T cells. E-cadherin is expressed by normal epithelial cells, Langerhans cells, and keratinocytes and is usually down-regulated on metastatic cancer cells. KLRG1 ligation by E-cadherin in healthy tissue may thus exert an inhibitory effect on primed T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The killer cell lectin-like receptor G1 (KLRG1)4 belongs to the C-type lectin superfamily that includes the families of Ly49, NKrp1, CD94-NKG2A/C/E, and NKG2D receptors. The human KLRG1 gene maps to the NK gene complex (1) while the murine homolog is located ~2 cM distant from it (2). KLRG1 was first identified in the rat basophilic leukemia cell line RBL-2H3 and was originally termed mast cell function-associated Ag (MAFA) (3). In uninfected mice, KLRG1 is expressed by ~30% of NK cells and by a few (2–10%) {alpha}beta T cells. Infection of mice with viruses or parasites leads to a substantial increase in KLRG1 expression by NK, CD4, and CD8 T cells (4, 5, 6, 7, 8). Expression of KLRG1 by NK cells is down-regulated in MHC class I-deficient mice; however, no binding between classical MHC class I molecules and KLRG1 has been found (9). In humans, KLRG1 is expressed by CD56dim NK cells (50–80%) and by CD4 (~20%) and CD8 (~40%) {alpha}beta T cells that exhibit an effector or an effector memory cell phenotype (10). The function of KLRG1 in vivo is not yet fully understood. The present study was aimed at identifying ligands for murine KLRG1 to allow a better understanding of the physiological role of this interesting molecule.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Synthesis of KLRG1 tetramers

A recognition site for enzymatic biotinylation was engineered by PCR to the 5' end of the entire extracellular domain of murine KLRG1 using a full-length KLRG1 cDNA as a template and the following oligonucleotide primers: 5'-CTC GAG CTG AAC GAC ATC TTC GAG GCT CAA AAG ATC GAG TGG CAC TAT CAA CGG ATC CTG TGC TGC-3' and 5'-CTC GAG TCA GTA TAG GAC CTT CTT ACA GAT CC-3'. The PCR fragment was digested by XhoI and cloned into pET-15b (Novagen). After verification of the sequence, the protein was expressed in Escherichia coli BL21 (DE3)pLysS. The recombinant protein was purified from inclusion bodies, biotinylated with BirA-Ligase (Avidity), and multimerized with streptavidin-PE (Molecular Probes) using standard procedures (11).

Screening of cDNA library

cDNA from BM-DC (day 8) was generated from poly(A)+ RNA. Generation of the Sindbis virus BM-DC cDNA library, sorting, RT-PCR, and sequencing were performed as described previously (12). For confirmation, 293T cells were transfected with full-length E-cadherin cDNA obtained from RIKEN Bioresource Center.

Mice

C57BL/6JOlaHsd (B6) mice were obtained from Harlan Winkelmann. P14 TCR-tg mice (B6;D2-Tg(TcrLCMV)318Sdz/JDvsJ) specific for aa 33–41 (= gp33 epitope) of lymphocytic choriomeningitis virus (13) and KLRG1-tg mice (B6,CBA/J-Tg(Klrg1)1Dhr (9) have been described previously.

Cell lines and cultures

293T cells and B16.BL6 cells were transfected by PolyFect reagent (Qiagen) with pCEP-GWA or modified pEF-BOS expression vectors (14) containing murine E-cadherin cDNA obtained from expression cloning or from RIKEN Bioresource Center, respectively. Cells were selected in medium containing 1.5 µg/ml puromycin (Sigma-Aldrich) or 1.2 mg/ml G418 (PAA), respectively. BM-DC were generated in vitro as described elsewhere (15). Lymphokine-activated killer (LAK) cells were prepared by incubating spleen cells (2 x 106/ml) for 3 days in medium containing 1 µg/ml human IL-2. In vitro T cell stimulation was performed by culturing 2 x 105 P14.KLRG1 T cells with 5 x 104 gp33 peptide-pulsed (10–6 M, 1 h, 37°C) B16.BL6 cells in 24-well plates for 3 days. P14.KLRG1 effector cells were generated by stimulating 2 x 105 P14.KLRG1 T cells with 105 gp33 peptide-loaded BM-DC in 24-well plates for 3 days.

Flow cytometry

Cells (105–106/100 µl) were stained with KLRG1 tetramers (0.1–1 µg/100 µl) and with appropriately diluted mAb at 4°C for 30 min. Abs were purchased from BD Pharmingen. Murine E-cadherin was stained with mAb ECCD-2 (Zymed Laboratories), followed by PE-labeled goat anti-rat IgG (Caltag Laboratories). Human E-cadherin was detected by mAb SHE78-7 (Alexis Biochemicals) and PE-labeled goat anti-murine IgG (Caltag Laboratories). Intracellular IFN-{gamma} staining of in vivo-generated P14 memory T cells was performed as described previously (7). Briefly, 2 x 106 P14 memory cells were stimulated with 3 x 105 gp33 peptide-pulsed B16.BL6 cells in 24-well plates for 5 h. Samples were analyzed by a BD FACSCalibur flow cytometer (BD Biosciences) using CellQuest-Pro software (BD Biosciences). Cell sorting was performed on a MoFlow (DakoCytomation). After the sort, purified KLRG1+NK1.1+ LAK cells were incubated overnight at 37°C to allow re-expression of KLRG1 before performing 51Cr release assays.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
E-cadherin is a ligand for murine KLRG1

Fluorescently labeled, soluble tetrameric complexes of the extracellular domain of the KLRG1 molecule were generated to identify cell types that express KLRG1 ligands. By screening various cell types, we found that in vitro-generated bone marrow-derived CD11c+ dendritic cells (BM-DC) could be stained brightly by KLRG1 tetramers. The tetramers also stained ex vivo-isolated CD11c+ Langerhans cells and a subset of CD11c+CD11b– plasmacytoid DC, but not CD11b+ macrophages derived from bone marrow cell cultures (Fig. 1A).


Figure 1
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  		FIGURE 1. E-cadherin is a ligand for KLRG1. A, In vitro-generated BM-DC, freshly isolated Langerhans cells (LC), in vitro-generated plasmacytoid DC (BM-PDC), and macrophages (BM-M{phi}) were stained with KLRG1 tetramers and the mAb indicated. The dot plots of BM-DC, Langerhans cells, and BM-derived macrophages were gated on total live cells, while BM-derived plasmacytoid DC were gated on CD11c+ cells. B, 293T cells were transfected transiently (top) or stably (bottom) with murine E-cadherin cDNA. Cells were stained with KLRG1 tetramers and with anti-E-cadherin mAb (open histograms). Filled histograms represent negative control staining.

 
To clone the ligand(s) recognized by KLRG1 tetramers, a Sindbis virus-based cDNA expression cloning system was used (12). Briefly, single-cell sorting of baby hamster kidney cells infected with Sindbis virus expressing a cDNA library from BM-DC was used to isolate clones that bound KLRG1 tetramers. Two independent clones were identified that stained positive with KLRG1 tetramers, and sequencing revealed that both contained cDNA fragments encoding murine E-cadherin. To confirm this result, 293T cells were transfected with full-length E-cadherin cDNA. Fig. 1B shows that 293T cells transiently or stably transfected with E-cadherin could be stained with both anti-E-cadherin Abs and KLRG1 tetramers.

Binding characteristics of KLRG1 tetramers

Parallel staining of BM-DC cultures with KLRG1 tetramers and anti-E-cadherin Abs yielded a remarkable similar pattern (Fig. 2A). Furthermore, pretreatment of BM-DC with trypsin, in the presence of EDTA but not in the presence of Ca2+, completely abolished KLRG1 tetramer staining (Fig. 2B). The Ca2+-dependent resistance of E-cadherin to trypsin degradation is a characteristic feature of this molecule (16). Ab blocking experiments further revealed that KLRG1 tetramer staining could be partially inhibited by the E-cadherin-specific mAb ECCD-1 (Fig. 2C, left). No inhibition was observed with another mAb (ECCD-2) that recognizes a different epitope on E-cadherin (Fig. 2C, right). Human and murine E-cadherin share 89% amino acid identity. It was therefore of interest to test whether murine KLRG1 tetramers also exhibited binding capacity to human E-cadherin. The tetramers also stained MDA-MB-435S breast carcinoma cells transfected with human E-cadherin cDNA (17) (Fig. 2D), while E-cadherin-negative parental cells were not stained (data not shown).


Figure 2
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  		FIGURE 2. Binding characteristics of KLRG1 tetramers. A, BM-DC cultures (day 8) were stained in parallel with KLRG1 tetramers and with anti-E-cadherin mAb. B, BM-DC cultures were pretreated for 30 min at 37°C with trypsin (0.25%) in the presence of 1 mM EDTA (left) or 1 mM CaCl2 (right). Afterward, cells were stained with the KLRG1 tetramer. C, BM-DC cultures were first incubated with (dotted line) or without (solid line) anti-E-cadherin mAb ECCD-1 (left) or ECCD-2 (right), respectively. Afterward, cells were stained with KLRG1 tetramers. D, Stable human E-cadherin transfectants of MDA-MB-435S cells were stained with KLRG1 tetramers and with anti-human E-cadherin mAb (open histograms). Filled histograms in C and D represent negative control staining.

 
E-cadherin expression by B16.BL6 target cells does not affect the cytolytic activity of LAK cells

To examine whether E-cadherin expression by target cells interfered with NK cell-mediated lysis, stable E-cadherin transfectants of the NK cell-susceptible B16.BL6 melanoma cells were established. B16.BL6.E-cadherin transfectants expressed high levels of E-cadherin on their cell surface while mock-transfected cells could not be stained with anti-E-cadherin mAb (Fig. 3A). NK cells were induced by culturing spleen cells from B6 and KLRG1-tg mice in the presence of IL-2 in vitro (LAK cells). In line with previous data (5), KLRG1 was expressed by the majority (>80%) of NK1.1+CD3– cells in these cultures (Fig. 3B). The results of the 51Cr release assays were clear-cut: E-cadherin and mock-transfected B16.BL6 target cells were lysed equally by these NK cells (Fig. 3C). This was true for LAK cells generated from B6 or from KLRG1-tg mice. Moreover, the same result was obtained when FACS-purified KLRG1+NK1.1+ LAK cells from KLRG1-tg mice were used (Fig. 3, B and C, right panels).


Figure 3
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  		FIGURE 3. Ectopic expression of E-cadherin by B16.BL6 target cells does not affect cytolytic NK cell activity. A, Stable E-cadherin and mock transfectants of B16.BL6 cells were stained with anti-E-cadherin mAb (dotted line). Filled histograms represent negative control staining. B, LAK cells, generated by culturing splenocytes from B6 and B6.KLRG1-tg mice for 3 days in medium containing IL-2, were analyzed by flow cytometry using the mAb indicated. Dot plots were gated on CD3-negative lymphocytes. Right, Re-analysis of cell-sorted KLRG1+NK1.1+ LAK cells. C, The LAK cells indicated were tested in 4-h 51Cr release assays using mock ({circ})- or E-cadherin-transfected (•) B16.BL6 target cells.

 
This result is in line with a previous report that failed to observe an inhibitory effect of anti-KLRG1 Abs on NK cell function (5), but is at odds with a previous study reporting inhibition of NK cell-mediated cytotoxicity by KLRG1 ligation (18). It is, however, important to stress that the latter study was performed with a NK cell clone overexpressing KLRG1.

E-cadherin expression inhibits Ag-induced cell division and induction of cytolytic activity of CD8 T cells

Next, we tested whether E-cadherin expression by target cells influenced the cytolytic activity of effector CD8 T cells. For these experiments, CD8 T cells from P14 TCR x KLRG1 double-transgenic mice (P14.KLRG1) were used that constitutively express KLRG1 and bear a TCR specific for the gp33 epitope of lymphocytic choriomeningitis virus. P14.KLRG1 effector cells were generated in vitro by stimulation of P14.KLRG1 splenocytes with gp33 peptide-loaded BM-DC. As target cells, E-cadherin and mock-transfected B16.BL6 cells were used that were loaded with the cognate gp33 peptide. Fig. 4A shows that gp33 peptide-loaded B16.BL6 target cells were efficiently lysed by P14.KLRG1 effector cells, irrespective of E-cadherin expression. The effect of E-cadherin expression on gp33-induced IFN-{gamma} production was further examined using in vivo-generated P14 memory T cells (7) expressing endogenous KLRG1. The experiments revealed that expression of E-cadherin on gp33 peptide-loaded B16.BL6 cells did not affect the ability of KLRG1+ P14 memory T cells to produce IFN-{gamma} (Fig. 4B).


Figure 4
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  		FIGURE 4. E-cadherin expression inhibits Ag-induced cell division and induction of cytolytic activity of CD8 T cells. A, P14.KLRG1 T cells induced by stimulation with gp33 peptide-pulsed BM-DC were used as effector cells in a 4-h 51Cr release assay. As target cells, stable E-cadherin- or mock-transfected B16.BL6 target cells were used that were loaded with gp33 (• and {blacktriangleup}) or control adenovirus E1A peptides ({circ} and {triangleup}). B, In vivo-generated P14 memory T cells were stimulated with either gp33 peptide-pulsed E-cadherin- or mock-transfected B16.BL6 cells. IFN-{gamma} secretion was determined by intracellular and KLRG1 expression by cell surface staining. Dot plots were gated on Thy1.1+ P14 memory T cells. C, P14.KLRG1 T cells were labeled with CFSE and were stimulated with gp33 peptide-pulsed E-cadherin (left)- or mock-transfected (right) B16.BL6 cells. After 3 days, cells were harvested and analyzed by flow cytometry. CFSE profiles of gated CD8 T cells are shown. As indicated, cultures were also performed in medium containing anti-KLRG1 mAb (10 µg/ml). D, P14.KLRG1 T cells were stimulated with gp33 peptide-pulsed E-cadherin (•)- or mock-transfected ({circ}) B16.BL6 cells in the absence (left) or in the presence (right) of anti-KLRG1 mAb. After 2 days, cells were harvested and cytolytic activity was determined using gp33 peptide-pulsed EL-4 target cells. Lysis of EL-4 cells pulsed with a control peptide was <5%. E, P14.KLRG1 T cells were stimulated with gp33 peptide-pulsed BM-DC in the absence (top) or in the presence (bottom) of anti-KLRG1 mAb. CFSE profiles of CD8 T cells at day 3 of in vitro culture are shown.

 
To determine whether interaction of KLRG1 with E-cadherin affects T cell proliferation, CFSE-labeled P14.KLRG1 T cells were stimulated with gp33 peptide loaded onto either E-cadherin- or mock-transfected B16.BL6 cells, and cell division was assessed by dilution of the CFSE label at day 3. Interestingly, Ag-induced cell division of P14.KLRG1 cells was significantly inhibited by the presence of E-cadherin on B16.BL6 cells. Importantly, this inhibitory effect could be reversed by adding anti-KLRG1 mAb to the culture medium (Fig. 4C). Finally, induction of cytolytic activity of P14.KLRG1 T cell cultures stimulated with gp33 peptide-pulsed B16.BL6 cells was examined. Strikingly, P14.KLRG1 T cells stimulated with B16.BL6.E-cadherin cells failed to lyse gp33 peptide-pulsed target cells, while efficient killing was observed with cultures stimulated with mock-transfected B16.BL6 (Fig. 4D, left). Moreover, addition of anti-KLRG1 mAb to the culture medium reversed this inhibitory effect (Fig. 4D, right). Thus, expression of E-cadherin on APC did not influence immediate effector cell functions but inhibited Ag-induced cell proliferation and induction of cytolytic activity of KLRG1+ CD8 T cells.

gp33 peptide-loaded BM-DC efficiently induced P14.KLRG1 effector cells despite E-cadherin expression (Fig. 4A) and addition of anti-KLRG1 mAb did not affect P14.KLRG1 cell division under these stimulating conditions (Fig. 4E). B16.BL6 melanoma cells are clearly less potent APC than in vitro-generated BM-DC. Therefore, these findings support the notion that the inhibitory effect of KLRG1 ligation is subtle and may be overruled by strong activation signals. In addition, our results fit well to earlier data that showed that Ab ligation of murine KLRG1 on T cells slightly reduced Ca2+ mobilization, but failed to substantially affect cytolytic activity (6).

In vivo, E-cadherin is found on epithelial cells, Langerhans cells, and keratinocytes (19, 20), all cell types that do not represent professional APC for naive T cells. Nonetheless, these cells can present foreign or self-Ags to primed CD8 T cells. E-cadherin on these cells could thus exert an inhibitory effect on KLRG1+ T cells, thereby preventing an exaggerated immune response. Similarly, NK cell activation in the course of an infection may also be modulated by E-cadherin-expressing cells. Noteworthily, E-cadherin also represents a ligand for the integrin heterodimer CD103 ({alpha}E/beta7) (21). The identification of E-cadherin as a ligand for KLRG1 should now promote new experimental approaches to further elucidate the function of KLRG1 in vivo.


   Acknowledgments
 
We thank Heike Unsöld, Marie Koschella, and Stephen Batsford for critical reading of this manuscript. We also thank Andreas Diefenbach for providing B16.BL6 cells and Herman Eibel for the modified pEF-BOS expression vector.


   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 the Deutsche Forschungsgemeinschaft (SFB620, Teilprojekt B2 to H.P., and HA2456/3.1 to T.H.). Back

2 Current address: TeGenero AG, Würzburg, Germany. Back

3 Address correspondence and reprint requests to Dr. Hanspeter Pircher, Institute of Medical Microbiology and Hygiene, Hermann-Herder-Strasse11, D-79104 Freiburg, Germany. E-mail address: hanspeter.pircher{at}uniklinik-freiburg.de Back

4 Abbreviations used in this paper: KLRG1, killer cell lectin-like receptor; BM-DC, bone marrow-derived dendritic cell; tg, transgenic; LAK, lymphokine-activated killer cell. Back

Received for publication August 8, 2005. Accepted for publication November 28, 2005.


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

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A. L. Floc'h, A. Jalil, I. Vergnon, B. L. M. Chansac, V. Lazar, G. Bismuth, S. Chouaib, and F. Mami-Chouaib
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Epithelial-mesenchymal transition process in human embryonic stem cells cultured in feeder-free conditions
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C. Baron, M.-C. Meunier, E. Caron, C. Cote, M. J. Cameron, D. J. Kelvin, R. LeBlanc, V. Rineau, and C. Perreault
Asynchronous Differentiation of CD8 T Cells That Recognize Dominant and Cryptic Antigens
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D. Masopust, S.-J. Ha, V. Vezys, and R. Ahmed
Stimulation History Dictates Memory CD8 T Cell Phenotype: Implications for Prime-Boost Vaccination
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M. Colonna
Cytolytic responses: cadherins put out the fire
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