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*
Institute of Immunology, Vienna International Research Cooperation Center, Novartis Research Institute, Vienna, Austria; and
Institute of Immunology,
Department of Internal Medicine III, Division of Rheumatology, and
§
Department of Dermatology I, University of Vienna, Vienna, Austria
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, stem
cell factor, and Flt3 ligand) is associated with pronounced cell
cluster formation of developing LC precursor cells. This
cell-clustering phenomenon requires hemopoietic progenitor cell
differentiation, since it is first seen on day 4 after culture
initiation of CD34+ cells. Cell cluster formation
morphologically indicates progenitor cell development along the LC
pathway, because parallel cultures set up in the absence of exogenous
TGF-ß1 fail to form cell clusters and predominantly give rise to
monocyte, but not LC, development (CD1a-,
lysozyme+, CD14+). TGF-ß1 costimulation of
CD34+ cells induces neoexpression of the homophilic
adhesion molecule E-cadherin in the absence of the E-cadherin
heteroligand CD103. Addition of anti-E-cadherin mAb or mAbs to any
of the constitutively expressed adhesion molecule (CD99, CD31, LFA-1,
or CD18) to TGF-ß1-supplemented progenitor cell cultures inhibits LC
precursor cell cluster formation, and this effect is, with the
exception of anti-E-cadherin mAb, associated with inhibition of LC
generation. Addition of anti-E-cadherin mAb to the culture allows
cell cluster-independent generation of LC from CD34+ cells.
Thus, functional E-cadherin expression and homotypic cell cluster
formation represent a regular response of LC precursor cells to
TGF-ß1 stimulation, and cytoadhesive interactions may modulate LC
differentiation from hemopoietic progenitor
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Differentiated epidermal LC share with epithelial cells of various organs high cell surface expression levels of the homophilic calcium-dependent cytoadhesion molecule E-cadherin (4, 5). LC to keratinocyte adhesion (4) as well as homotypic adhesion of in vitro generated murine LC (6) can be blocked by mAbs to E-cadherin, suggesting an important role for E-cadherin in LC adhesion (reviewed in Ref. 2). Among DC, only differentiated LC and a subpopulation of DC from skin-draining lymph nodes, which may be derived from LC, express E-cadherin (7). E-cadherin expression is markedly down-regulated upon migration and maturation of epidermal LC, and lower expression levels of E-cadherin on the surfaces of cultured LC correlate with decreased cell adhesiveness (4, 7, 8). Apart from LC-type DC, most other hemopoietic cells, with the exception of immature thymocytes (9, 10), murine dendritic epidermal T cells (11), and immature erythroid cells (12), lack E-cadherin expression.
The cytokine TGF-ß1 plays a key role during LC development and differentiation. Using an in vitro differentiation model of CD34+ hemopoietic progenitor cells, we recently demonstrated that development of LC from CD34+ progenitor cells in a serum-free culture system is absolutely dependent on TGF-ß1 stimulation (13). In vivo studies revealed that TGF-ß1-deficient mutant mice selectively lack epidermal LC (14), but possess functional LC precursors (15) and other myeloid cells and show normal bone marrow morphology (16). Bone marrow cells from TGF-ß1-deficient mice are capable, upon transplantation into normal mice, of differentiating into LC, suggesting that paracrine TGF-ß1 stimulation of LC precursors in peripheral organs is sufficient for LC differentiation in vivo (15). Furthermore, similar numbers of bone marrow-derived LC were identified in TGF-ß1-/- and control skin after engraftment onto nude mice. Additionally, epidermal-restricted TGF-ß type II receptor dominant negative transgenic mice contain normal numbers of LC (15). These observations suggest that the LC deficiency in TGF-ß1-/- mice reflects a requirement of LC or precursor cells for TGF-ß1 and is obviously not due to modulation of the cutaneous microenvironment. This model seems to be compatible with a critical role for endogenous TGF-ß1 in LC development. In line with this possibility, LC-type DC are known to synthesize TGF-ß1 abundantly (6, 17, 18), and a recent study showed that TGF-ß1-transduced DC show increased survival and persistence after transplantation into normal allogeneic mice (19). The mechanisms involved in TGF-ß1-dependent LC differentiation, however, remained unclear.
Here we demonstrate that LC development from CD34+ hemopoietic progenitor cells in response to TGF-ß1 stimulation is associated with pronounced homotypic cell cluster formation of cultured cells. This cell-clustering phenomenon is mediated by TGF-ß1-induced E-cadherin in cooperation with several constitutively expressed adhesion molecules. Cluster inhibition studies suggest that TGF-ß1-dependent cellular interactions may be functionally involved in LC differentiation from their precursor cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The following murine mAbs were generated in our laboratory: VIAP (nonbinding isotype control Ab, calf intestine alkaline phosphatase specific), LZ-1 (human lysozyme), VIT6b (CD1a), 5E6 (CD11a), and 3B2/TA8 (CD99). CD14 mAb MEM-18 was provided by An der Grub (Kaumberg, Austria); CD34 mAb HPCA2 was obtained from Becton Dickinson (San Jose, CA); CD18 mAb TS1/18 was purchased from American Type Culture Collection (Manassas, VA); CD11b mAb 2LPM19C was obtained from Dako (Glostrup, Denmark). CD29 mAb 4B4, CD49d mAb HP2/1, CD49e mAb SAM1, and CD103 mAb 2G5 were obtained from Beckman Coulter (Fullerton, CA). E-cadherin mAb HECD-1 was purchased from Zymed (San Francisco, CA); CD31 mAb CLB-HEC/75 was purchased from CLB (Amsterdam, The Netherlands).
The following above-mentioned Abs were used in cell culture experiments. They were selected based on previously published functional studies: clone VIAP (control Ab, IgG1, purified from ascites using protein A chromatography) (20), clone 5E6 (CD11a, IgG1, purified from ascites fluid using protein A chromatography, cell adhesion-blocking mAb) (20), clone 3B2/TA8 (CD99, IgG1, purified from ascites fluid using protein A chromatography, mitogenic signaling mAb) (21), clone TS1/18 (CD18, IgG1, purified from hybridoma supernatant using protein A chromatography, cell adhesion-blocking mAb) (22), clone 4B4 (CD29, IgG1 purified from ascites fluid using ion exchange chromatography, cell adhesion-blocking mAb) (23), clone HP2/1 (CD49d, IgG1, purified from hybridoma supernatant using affinity purification, cell adhesion-blocking mAb) (24), clone SAM1 (CD49e, IgG1, purified from hybridoma supernatant using affinity purification, cell adhesion-blocking mAb) (25), clone HECD-1 (E-cadherin, IgG1, purified from ascites fluid using ammonium sulfate precipitation, cell adhesion-blocking mAb) (26) and clone CLB-HEC/75 (CD31, IgG1 purified from ascites fluid using affinity chromatography, cell adhesion-blocking mAb) (27). Before functional analysis, all Abs were dialyzed against serum-free cell culture medium (see below). Abs were added to cultures at a final concentration of 20 µg/ml. Ab preparations, which were used in cell culture experiments, were tested for endotoxin (LPS). All the mAbs tested contained <0.1 ng/ml LPS, with the exception of mAb HEC/75 (CD31), which contained low levels of endotoxin (3.5 ng/ml). Because all experiments were performed in serum-free medium, which does not contain significant amounts of LPS binding protein and soluble CD14, it is very unlikely that the observed functional effect of the mAb HEC/75 is due to LPS contamination.
Immunofluorescence staining procedures
For membrane staining, 50 µl of cells (107/ml) were incubated for 15 min at 4°C with 20 µl of conjugated mAb or unconjugated mAb. For staining using unconjugated mAb, FITC-conjugated F(ab')2 of sheep anti-mouse Ig Abs (An der Grub) were used as described previously (28). Cells were washed and analyzed by flow cytometry or were subjected to intracellular staining.
For suspension staining of the intracellular Ags, we used the commercially available reagent combination Fix&Perm (An der Grub) according to the manufacturer’s directions. Briefly, cells are fixed for 15 min at room temperature (50 µl of cells plus 100 µl of formaldehyde-based Fixation Medium). After one washing with PBS, pH 7.2, cells are resuspended in 50 µl of PBS and mixed with 100 µl of Permeabilization Medium plus 20 µl of fluorochrome-labeled Ab. After a further incubation for 15 min at room temperature, cells are washed again and analyzed by flow cytometry. Flow cytometric analyses were performed using a FACScan flow cytometer (Becton Dickinson).
Cord blood (CB) cells
CB samples were collected during normal full-term deliveries. Mononuclear cells were isolated within 10 h after collection using discontinuous Ficoll/Hypaque (Pharmacia, Uppsala, Sweden) density gradient centrifugation. CD34+ cells were isolated from CB mononuclear cells using the MACS CD34 Progenitor Cell Isolation Kit (Miltenyi Biotec, Bergisch Gladbach, Germany) according to the instructions of the manufacturer. The purity of the CD34+ population exceeded 90%.
Primary cultures of purified CD34+ CB cells
Primary cultures of purified CD34+ CB
cells were performed in 24-well plates (Costar, Cambridge, MA; 1
x 104 cells in 1 ml/well) at 37°C in a
humidified atmosphere and in the presence of 5%
CO2 as described previously (29).
The serum-free medium X-VIVO 15 (BioWhittaker, Walkersville, MD)
contained L-glutamine (2.5 mM), penicillin (125 U/ml), and
streptomycin (125 µg/ml). Cultures were supplemented with optimized
concentrations of the following human cytokines: Flt3 ligand (FL; 100
ng/ml; provided by Immunex, Seattle, WA), TGF-ß1 (0.5 ng/ml; purified
from platelets; British Biotechnology, Abington, U.K.), rTNF- (50
U/ml; Bender, Vienna, Austria), rGM-CSF (100 ng/ml; Novartis, Basel,
Switzerland), and recombinant human stem cell factor (SCF; 20 ng/ml;
Amgen, Thousand Oaks, CA).
Monoclonal Ab stimulation experiments of CD34+ cells
Primary cultures of CD34+ cells were set up exactly as described above. After 24 h cells were harvested and replated in duplicate in 96-well plates containing identical growth media at a cell density of 1 x 104 cells/well. Cultures were supplemented with 20 µg/ml mAb when indicated, and plates were incubated at 4°C to allow Ab binding. Afterward, cells were transferred to 37°C and cultured for 7 days. On days 3 and 7, cultures were analyzed for cell cluster formation by phase contrast microscopy using a scoring system previously established in our laboratory (20) with slight modifications. Scores ranged from 0 to 4; 0 indicated that <10% of the cells were in aggregates, 1 represented 10–50% aggregated cells, 2 indicated that about 50–75% of the cells were aggregated, 3 indicated 75- 90% of the cells were aggregated, and 4 indicated that >90% of the cells were found in large aggregates. On day 7 cells were harvested and analyzed by flow cytometry (see above).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We recently established a serum-free culture system for the
efficient generation of Birbeck granule Ag
Lagbright, CD1abright LC
from human CD34+ progenitors and observed that LC
generation is strictly dependent on addition of TGF-ß1 to the culture
medium (29) containing the classical DC cytokines GM-CSF
plus TNF-, SCF, and FL (30, 31, 32).
As shown in Fig. 1
(upper
panel), TGF-ß1-dependent LC growth observed in this defined
culture system is associated with the formation of large cell clusters.
In the absence of TGF-ß1 (Fig. 1, lower panel) cells do
not form or form only few, very small, cell clusters and do not
differentiate into CD1a+ LC (Fig. 1, lower panel).
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In line with the selective generation of LC in the presence of
TGF-ß1, only a minor portion of cultured cells show monocytic
features (LZ+, CD1a-; Fig. 1
, upper right). Conversely, a large portion of cells
generated in TGF-ß1-nonsupplemented cultures develops into
LZ+CD1a- monocytic cells
(Fig. 1, lower right). These data suggest an association of
TGF-ß1-induced cluster formation and LC differentiation.
TGF-ß1 induces expression of the homophilic adhesion molecule E-cadherin
As described above, TGF-ß1-induced LC differentiation is
strictly associated with cell cluster formation, suggesting regulation
of adhesion molecule expression by TGF-ß1. The homophilic epithelial
adhesion molecule E-cadherin is known to be expressed in vivo not only
by epithelial cells but also by LC (5), and mediates high
affinity binding of LC to keratinocytes (4). As shown in
Fig. 1, the vast majority of CD1a+ cells in vitro
generated in the presence of TGF-ß1 strongly express E-cadherin.
Cells generated in the absence of TGF-ß1 remain
E-cadherin-, except for a small
E-cadherin+CD1a-
subset.
Fig. 2 shows representative expression
profiles of a panel of cytoadhesion molecules by cells generated in the
presence or the absence of TGF-ß1. As shown, CD103 (HML-1, integrin
E chain), which associates with the ß
subunit of the heterodimer integrin
Eß7, a heteroligand of
E-cadherin (33), could not be detected on the surface of
generated cells. Most cells generated in the presence or the absence of
TGF-ß1 express the ß1 integrins CD49d/CD29
(VLA-4) and CD49e/CD29 (VLA-5) as well as the
ß2 integrin CD11a/CD18 (LFA-1); <10% of cells
express the ß2 integrin -chain CD11b (data
not shown). Additionally a subset of generated cells expresses CD31
(PECAM-1), and most cells express CD99 (MIC-2/E2). All these latter
molecules are already expressed at the CD34+
progenitor cell stage (34), and their expression pattern
is not significantly affected by TGF-ß1 stimulation. In contrast,
E-cadherin is clearly induced by TGF-ß1 stimulation and cannot be
detected on the cell surface of CD34+ hemopoietic
progenitors (12).
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To analyze whether TGF-ß1-induced LC differentiation and cell cluster formation are functionally linked, we performed cell cluster inhibition experiments using blocking mAbs to adhesion molecules and studied whether cell cluster inhibition may affect LC differentiation in TGF-ß1-supplemented LC generation cultures.
Addition of mAb 3B2/TA8 or TS1/18, specific for CD99 or the common
ß-chain of ß2 integrins (CD18), respectively, strongly inhibited LC
cluster formation when added on day 1 to TGF-ß1-supplemented LC
generation cultures. As shown in Fig. 3,
cultures supplemented with mAbs TS1/18 or 3B2/TA8 contained no or only
very small cell clusters.
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).
Thus, mAb 3B2/TA8 binding to CD99 not only inhibits cluster formation,
but the overall differentiation pattern of CD34+
progenitor cells switches from LC to monocytes. Very similar effects on
differentiation were observed in cultures containing the CD18 mAb
TS1/18 (14.7 ± 2.9% of CD1a+ cells and
55.6 ± 8.8% of LZ+
CD1a- cells; Fig. 4). A shift in the lineage
differentiation pattern from LC to monocytic cells was confirmed by the
observation that substantial percentages of cultured cells in the
presence of mAbs 3B2/TA8 or TS1/18 express the monocyte marker molecule
CD14 in the absence of CD1a (33.7 ± 9.1 and 24.5 ± 8.8%,
respectively; n = 3; see Fig. 4). The numbers of cells
recovered on day 7 from Ab-supplemented cultures initiated with 1
x 104 CD34+ cells on day 0
did not differ significantly (mAb 3B2/TA8, 20.8 ± 4.7 x
104; mAb TS1/18, 18.1 ± 4.8 x
104; control mAb VIAP, 25.1 ± 4.9 x
104; n = 4). The differentiation
pattern and morphology of cells generated in these cultures resemble
those of cells cultured in the absence of TGF-ß1 (Fig. 1)
(29). Thus, addition of mAbs to these cytoadhesion
molecules inhibits TGF-ß1-induced cell cluster formation and LC
differentiation.
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Addition of mAb CLB-HEC/75 or 5E6, specific for CD31 or
LFA-1, respectively, also inhibited TGF-ß1-induced cell cluster
formation when added to TGF-ß1-supplemented LC generation cultures of
CD34+ cells. This effect was associated with
strong inhibition of cell proliferation. As shown in Fig. 5 cell numbers of cultured cells
continuously decreased from days 0 to 3 to 7 in cultures supplemented
with either of these mAbs. We previously demonstrated that TGF-ß1
exerts an anti-apoptotic effect on LC progenitor cells when added to
GM-CSF- plus TNF- and SCF-supplemented cultures of
CD34+ cells (36). Decreased
viability of LC precursors in the presence of these LC cluster-blocking
mAbs may, therefore, reflect a role of cell clustering in mediating an
anti-apoptotic activity of TGF-ß1 on cultured
CD34+ cells.
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Addition of mAb HECD-1 specific for E-cadherin on day 1 to
TGF-ß1-supplemented cultures of CD34+ cells
strongly inhibits cell cluster formation (Fig. 3). Phenotypic analyses
revealed that a large percentage of cells generated after 7 days,
however, express high levels of CD1a. As shown in the representative
phenotypic analyses in Fig. 4, E-cadherin mAb-supplemented cultures
contained reproducibly even higher percentages of
CD1a+ cells than control cultures (47.3 ±
2.9 vs 41.8 ± 2.1%; n = 4).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, SCF, and FL for 7 days fail to form
cell clusters and predominantly develop into monocytic cells. Addition
of TGF-ß1 to these short term cultures results in pronounced cell
cluster formation and a concomitant shift in the differentiation
pattern of stimulated CD34+ cells from monocytic
progeny to LC-type DC. This LC differentiation-linked cell-clustering
phenomenon starts on day 4 after culture initiation of purified
CD34+ cells and thus obviously requires the
pregeneration of a committed precursor cell population. These data
suggest that cell clustering may mark an early branching point at which
monocyte/LC precursor cells start to differentiate into LC. In support
of this assumption, we previously observed that
CD1a+ LC in TGF-ß1-supplemented cultures seem
to develop from a day 4 generated early monopoietic precursor cell
population (13) identifiable by the expression of lysozyme
in the absence of CD14 (35). Furthermore, recent studies
demonstrated that even later stage CD14+
precursor cells can be induced to differentiate into LC in response to
TGF-ß1 costimulation (37, 38, 39), thus supporting this
possibility. Homophilic E-cadherin interactions between developing LC precursor cells seem to be critically involved in the TGF-ß1-induced, early appearing, cell-clustering phenomenon of developing LC precursor cells described herein. First, large proportions of cells from TGF-ß1-supplemented cultures express E-cadherin at high levels, whereas most cells from TGF-ß1-nonsupplemented parallel cultures lack E-cadherin expression (with the exception of a small E-cadherindim subset). Second, physical separation of clustered cells from TGF-ß1-supplemented LC generation cultures (by 1 x g sedimentation) results in strong enrichment of E-cadherin+ CD1a+ cells (data not shown). Third, addition of a blocking anti-E-cadherin mAb on day 1 to the cultures inhibits TGF-ß1-induced cell cluster formation. Furthermore, cells generated in TGF-ß1-supplemented LC generation cultures lack expression of CD103, a previously characterized heterophilic E-cadherin ligand (33). Thus, the cell cluster phenomenon described herein obviously involves homotypic LC precursor cell interactions, which are mediated by E-cadherin adhesion. Given the fact that E-cadherin has previously been described as a reliable surface marker molecule for developing LC-type DC in cultures of CD34+ cells (30), these observations seem to support above-mentioned tight linkage of cell cluster formation and LC differentiation in our culture model.
Ab blockage experiments revealed that in addition to E-cadherin, several constitutively expressed adhesion molecules are functionally involved in TGF-ß1-induced homotypic LC precursor cell clustering. We demonstrate that addition of mAbs to CD11a (LFA-1), CD18, CD31, or CD99 to day 1 cultures of CD34+ cells inhibits TGF-ß1-induced LC precursor cell clustering. Interestingly, in contrast to E-cadherin, all these latter adhesion molecules were previously shown to be constitutively expressed by freshly isolated CD34+ cells (reviewed in Ref. 34), and we observed that their expression intensities by cultured cells were only slightly modulated by TGF-ß1 costimulation.
The identification of several cell cluster-blocking mAbs allowed us to
study a possible functional linkage of cell cluster formation and LC
differentiation. Ab addition experiments indeed seem to argue in favor
of this possibility. We observed that inhibition of LC precursor cell
clustering by addition of certain mAbs to TGF-ß1-supplemented
progenitor cell cultures selectively inhibits LC generation. For
example, addition of mAb TS1/18 (CD18) or the mAb 3B2/TA8 (CD99)
inhibited LC development, and cells developed into
LZ+CD14+CD1a-
monocytic cells. From this differentiation pattern these cells
strikingly resembled cells generated in parallel cultures in the
absence of TGF-ß1 (Fig. 1). Thus, inhibition of cell cluster
formation by mAbs to these adhesion molecule systems seemed to be
associated with abrogation of the effects of TGF-ß1 on the
differentiation pattern of cultured cells. These data suggest, but do
not formally prove, a functional linkage of cell cluster formation and
LC differentiation in our culture model system. We cannot exclude the
possibility that functional activation of certain adhesion receptors in
response to mAb ligation may inhibit LC differentiation. Consistent
with this latter possibility, mAb 3B2/TA8 directed against CD99 was
previously demonstrated to induce a mitogenic cosignal for T
lymphocytes (21), and overexpression of CD99 promotes cell
cycling of B cell lines, whereas antisense blockage enforces
differentiation of these cells (40). With regard to a
possible role of CD99 signaling in modulating TGF-ß1-dependent
progenitor cell differentiation, CD34+ abundantly
express CD99 molecules (34). Thus, future studies should
analyze further the functional consequences of CD99 signaling on
cytokine-induced lineage differentiation of CD34+
cells.
Interestingly, mAb HEC/75 or 5E6 (directed against CD31 or CD11a, respectively) blocked TGF-ß1-induced LC precursor cell clustering of CD34+ cells, and this effect was associated with inhibition of cell proliferation early during culture. It is possible that CD31 and/or CD11a interactions are involved in initial TGF-ß1-induced cell cluster formation of CD34+ cells and may be functionally involved in mediating an anti-apoptotic (36) or (pro-) proliferative effect (39) of TGF-ß1 on LC precursor cells. Consistent with this possibility, both CD11a and CD31 molecules have previously been implicated in cell adhesion of hemopoietic progenitor cells. We previously demonstrated that mAb 5E6 (specific for CD11a; used in the present study) blocks CD34 ligation-induced homotypic cell clustering of the hemopoietic progenitor cell line KG1a (20). Lastres et al. (27) observed that CD31 mAb HEC/75 blocks TGF-ß1-induced cell clustering of the promonocytic cell line U-937. In line with our observations, CD31 is expressed at high levels by virtually all CD34+ cells, and transmigration of CD34+ cells (41) or a subset of CD34+ DC precursors (42) through vascular endothelial layers is dependent on CD31 adhesion.
As mentioned above, mAb HECD-1 directed against E-cadherin inhibited TGF-ß1-induced LC precursor cell cluster formation, but in contrast to the above cell cluster-blocking mAbs, outgrowth of CD1a+ LC was not impaired. These observations thus seem to argue against a functional involvement of cell clustering in LC differentiation. We cannot, however, rule out the possibility that E-cadherin ligation by mAb may functionally alter the differentiation pattern of cultured cells, eventually leading to enhancement of LC generation. Consistent with this possibility, E-cadherin has previously been implicated in the differentiation processes of epithelial (43) and hemopoietic progenitor cells (10, 12). Additionally, mAb ligation of E-cadherin on the surface of epithelial cell lines was previously shown to mimic homophilic E-cadherin ligation in inducing transmembrane signaling in epithelial cell lines (44, 45, 46).
In conclusion, cell cluster formation represents a regular response of LC precursor cells to TGF-ß1 stimulation, and TGF-ß1-dependent cellular interactions may modulate LC development and differentiation. This differentiation model is optimally suited for studying the possible functional involvement of E-cadherin in LC differentiation using gene transfer experiments.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Herbert Strobl, Institute of Immunology, University of Vienna, Borschkegasse 8A, A-1090 Vienna, Austria.
3 Abbreviations used in this paper: LC, Langerhans cells; SCF, stem cell factor; FL, Flt3 ligand; DC, dendritic cells; CB, cord blood.
Received for publication February 22, 2000. Accepted for publication May 23, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain (CD11b) potentially involved in intramembrane complex formation with glycosylphophatidylinositol-anchored Fc
RIIIB (CD16) molecules. J. Immunol. 154:5452.[Abstract]
. J. Exp. Med. 184:695.. J. Immunol. 154:5851.[Abstract]
Eß7 integrin. Nature 372:190.[Medline]
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