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E (CD103)-Deficient Mice1
*
Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany; and
Center for Animal Resources and Comparative Medicine, Harvard Medical School, Boston, MA 02115
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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E
7 is thought to
play an important role in the localization of mucosal, but not of
cutaneous T lymphocytes. Thus, it was surprising that 89% of adult
E-/- mice on the 129/Sv x BALB/c
background developed inflammatory skin lesions without an apparent
infectious etiology. Skin inflammation correlated with E
deficiency in mice with a mixed 129/Sv x BALB/c background, but
not in mice further backcrossed to BALB/c and housed in a second animal
facility. These studies suggested that E deficiency, in
combination with other genetic and/or environmental factors, is
involved in lesion development. The lesions were infiltrated by
CD4+ T cells and neutrophils, and associated with increased
expression of inflammatory cytokines. Furthermore, skin inflammation
resulted from transfer of unfractionated
E-/- splenocytes into
scid/scid mice, but not from transfer of wild-type
splenocytes, suggesting that the lesions resulted from immune
dysregulation. We also studied the role of
E7 in a murine model of
hyperproliferative inflammatory skin disorders that is induced by
transfer of minor histocompatibility-mismatched
CD4+/CD45RBhigh T cells into
scid/scid mice under specific environmental conditions.
Under housing conditions that were permissive for lesion development,
transfer of E-deficient
CD4+/CD45RBhigh T cells significantly
exacerbated the cutaneous lesions as compared with lesions observed in
mice reconstituted with wild-type donor cells. These experiments
suggested that E-expressing cells play an important role
during the course of cutaneous inflammation. In addition, they suggest
that E7 deficiency, in combination with
other genetic or environmental factors, is a risk factor for
inflammatory skin disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E (CD103) 7
is expressed by T lymphocytes in or adjacent to mucosal epithelia,
including 90% of CD8+ intestinal T cells in or
adjacent to the small intestinal epithelium, and 40–50% of the
CD4+ T cells within the intestinal lamina
propria. It binds to E-cadherin (1, 2, 3) on epithelial cells
and may be important in the localization of diffusely distributed T
cells within the intestinal epithelium. Integrin
E7 also is found on
dendritic epidermal T cells, some dendritic cells, some lymphomas and
leukemias, and bone marrow-derived mast cells (4, 5, 6, 7, 8, 9, 10)
cultured in the presence of TGF-1, a cytokine that also induced
E7 expression on T
lymphocytes (1, 11). Like other integrins, the avidity of
the interaction between
E7 and E-cadherin can
be regulated through inside-out signaling in response to T cell
stimulation with anti-CD3 (1, 11). In addition,
E7 appears to
transmit an outside-in signal, as some
anti-E mAbs enhance proliferation of T
cells in response to suboptimal concentrations of anti-CD3 or
induce the lysis of Fc receptor-bearing targets by
E7-expressing T
cells (7, 8). Thus,
E7 may also function
to modulate the response of T lymphocytes to stimulation by epithelial
cells, akin to the important accessory role of the integrin CD11a/CD18
(LFA-1) during peripheral T lymphocyte/APC interactions
(12, 13, 14).
Consistent with the proposed function of
E7 in intraepithelial
retention of mucosal T lymphocytes, we recently reported that integrin
E-deficient mice have reduced numbers of T
lymphocytes diffusely distributed within the intestinal and vaginal
epithelia (3). However, expression of E-cadherin, the
known ligand for E7,
is not restricted to mucosal epithelial cells, but is also found on
epithelial cells in the skin. Furthermore, expression of
E7 has been observed
in some cutaneous disorders, such as T cell lymphomas, lichen planus,
or atopic dermatitis (4, 15, 16, 17). However, it is unclear
whether E7
contributes to epidermal localization of T lymphocytes, and a role of
integrin E7 in the
cutaneous immune system and/or the generation of inflammatory skin
disorders has not been described.
In this study, we report the surprising observation that
nearly all E (CD103)-deficient mice
spontaneously developed inflammatory ulcerative skin lesions in our
initial cohort. This observation prompted further investigations toward
a potential function of
E7 on cutaneous T
cells and/or in the pathogenesis of inflammatory skin disorders.
Indeed, we found that
E7 significantly
influences the generation of hyperproliferative inflammatory skin
alterations in mice. These results suggest that the
E7 integrin performs
a function on T cells localized in the skin and may play a role in
hyperproliferative inflammatory skin disorders.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The generation and genotyping of mice deficient for the
E integrin subunit (CD103) have been described
previously (3). In reconstitution experiments,
C.B-17/lcrTac-scidfDFscid/scid
(scid/scid) mice (Taconic Farms, Germantown, NY) of 5–8 wk
of age were used as recipients. Mice were kept under specific
pathogen-free conditions in microisolator cages. Microbiologic
assessment of E-/- and
E+/+ mice included: Gram
stain of inflamed skin and eyelids; bacterial and fungal cultures of
blood, inflamed and uninflamed skin, and eyelids; and bacterial
cultures of nasopharyngeal washes that revealed growth of resident
flora including -streptococci, Pasteurella aerogenes,
Pasteurella multocida, Staphylococcus
epidermidis, and Streptococcus acidominimus. Additional
evaluation included anal tape test, fecal flotation, and microscopic
pelage for metazoan parasites, and serologies for murine viral
pathogens including Sendai virus, pneumonia virus of mice, mouse
hepatitis virus, minute virus of mice, GD-7 virus, Reo-3 virus,
lymphocytic choriomeningitis virus, mouse adenovirus, mouse pox virus
(ectromelia virus), K-virus, polyoma virus, epizootic diarrhea of
infant mice, mouse CMV, mouse thymic lymphocyte virus, and Hantaan
virus, and for procaryotic organisms including cilia-associated
respiratory bacillus, Encephalitozoon cuniculi, and
Mycoplasma pulmonis.
Antibodies
The following murine Ags were detected by mAbs: CD3
(500A2;
PharMingen, San Diego, CA), CD4 (RM4-5; PharMingen), CD8 (53-6.72;
American Type Culture Collection (ATCC), Manassas, VA), CD11b
(M integrin, Mac-1, M1/70; ATCC), CD18
(2 integrin, 2E6; ATCC), CD25 (IL-2R
-chain, 3C7; PharMingen), CD45R/B220 (RA3-6B2; PharMingen), CD45RB
(MB23G2, ATCC; 16A, PharMingen), CD49f (6
integrin, GoH3; Dianova, Hamburg, Germany), CD54 (ICAM-1, YN1/1.7.4;
ATCC), CD103 (E integrin, M290, P. Kilshaw
(Department of Immunology, AFRC Babraham Institute, Cambridge, U.K.)
(5), or 2E7, L. Lefrancois (Department of Medicine,
University of Connecticut Health Center, Farmington, CT)
(8)), 7 (M293; P. Kilshaw
(Department of Immunology, AFRC Babraham Institute, Cambridge, U.K.)),
CD106 (VCAM-1, M/K-2.7; ATCC), CD32/CD16 (Fc-
II/IIIR, 2.4G2; ATCC),
H-2Dd (34-2-12; PharMingen),
H-2Kb (AF6-88.5; PharMingen), MHC class II
(M5/114.15.2 or N22; ATCC), IFN- (XMG1.2; PharMingen), IL-4
(BVD6-24G2; PharMingen), IL-6 (MP5-20F3; PharMingen), GM-CSF (MP1-22E9;
PharMingen). In addition, rabbit antisera reactive with murine IL-1
and TNF- (Genzyme, Cambridge, MA) were used. The following mAbs were
used as controls: rat IgG1 (R59-40; PharMingen), rat IgG2a (R35-95;
PharMingen), rat IgG2b (SFR3-DR5; ATCC), and hamster IgG (UC8-4B3;
PharMingen). FITC anti-CD45RB (mAb 16A) and PE anti-CD4 (mAb
RM4-5) were obtained from PharMingen; biotinylated goat
anti-hamster, mouse-adsorbed rabbit anti-rat and goat
anti-rabbit serum were obtained from Vector Laboratories
(Burlingame, CA); and goat anti-rat Microbeads were purchased from
Miltenyi Biotec (Auburn, CA).
Histopathologic analysis and in vivo 5-bromo-2'-deoxyuridine (BrdU)3 labeling
For histochemical analysis, tissue samples were fixed, dehydrated, and embedded in JB-4 plastic resin according to the manufacturer’s instructions (Polysciences, Warrington, PA). Sections (3 µm) were stained with hematoxylin-eosin or for chloroacetate esterase reactivity, as described elsewhere (18, 19). Samples were evaluated by an investigator blinded to the mouse genotype. For immunohistochemistry, 5-µm acetone-fixed cryostat-cut sections were stained by indirect immunoperoxidase using an avidin-biotin complex (ABC) kit (Vector Laboratories) using 3-amino-9-ethylcarbazole (Aldrich, Milwaukee, WI). To detect proliferating cells, mice were injected i.p. with 5 mg BrdU in 500 µl PBS at both 9 and 6 h before sacrifice. JB-4 plastic-embedded sections were immersed in 0.03% H2O2 in methanol and denatured with 0.4% pepsin (Sigma, St. Louis, MO) in 0.1 N HCl and 0.8 N HCl. Sections then were stained with anti-BrdU (Becton Dickinson, Hamburg, Germany) and the ABC immunoperoxidase method. All immunohistochemical stainings were performed using tissue sections from at least three mice.
Cell purification and reconstitution of scid/scid mice
PBMCs from E+/+ and
E-/- mice were isolated by
density gradient centrifugation and H-2 typed, and mice homozygous for
the H-2Dd haplotype were used as donors. For
adoptive transfer experiments, splenocytes were isolated and passed
over a glass wool column to remove debris and to enrich for T cells. To
enrich for CD4+ or CD8+ T
lymphocytes, negative selection was performed with anti-CD4 or
anti-CD8 mAbs using a magnetic cell separation system according to
the manufacturer’s instructions (Miltenyi Biotec, Cologne, Germany).
The resulting populations were 
85% pure. In addition, contamination
of the CD4+ population with
CD8+ cells or of the CD8+
population with CD4+ cells was <1% in each
case, as determined by FACS.
C.B-17/IcrTac-scidfDFscid/scid recipient mice
were injected i.v. with 1.7–2 x 107 of
unfractionated splenocytes or with 2.2 x
106 CD4+- or
CD8+-enriched T cells. The ear thicknesses of the
recipient scid/scid mice were monitored over 6 wk, and
tissues were harvested for histopathologic analysis at the end of the
observation period.
For generation of psoriasiform skin lesions by reconstitution of
scid/scid mice with
CD4+/CD45RBhigh T
lymphocytes (18), splenocytes from
E+/+ or
E-/- donors that were MHC
matched, but minor histocompatibility Ag mismatched, were purified as
described previously (19, 20, 21). Briefly, splenocytes were
incubated with 20 µg each of anti-B220,
anti-M integrin, anti-CD8, and
anti-MHC class II mAbs/107 cells, followed by
20 µl goat anti-rat microbeads/107 cells
and stained cells were depleted using a magnetic cell separation system
separation column (type CS; Miltenyi Biotec). The
CD4+-enriched population then was incubated for
30 min with 7.5 µg PE-conjugated rat anti-CD4, and 12.5 µg
cells FITC-conjugated anti-CD45RB/107 cells.
Using a FACSvantage (Becton Dickinson), the 40–45% of cells
expressing the highest levels of CD45RB (naive T cells)
(22) were selected from the CD4+
population (hereafter referred to as
CD4+/CD45RBhigh T cells).
scid/scid recipient mice were injected with 2–2.5 x
105 cells each. Recipient mice started to develop
environmentally modulated psoriasiform skin lesions within 3–4 wk
(19, 23). Mice were weighed at weekly intervals. To
evaluate the overall skin inflammation, the ear thicknesses were
monitored using a skin thickness gauge (Oditest; Dyer, Lancaster, PA),
and a clinical score for the psoriasis-like skin disorder was applied
as described previously (19). Of note, mice developed
lesions in this model when they were fed mouse breeder chow with 9%
fat, kept in Pine Soft Wood Chips (100% virgin), and under static air
in microisolator cages with weekly airflow. However, lesions did not
develop if they were fed Prolab RMP3000, kept in Bed-o-cob bedding with
continuous air flow in the same animal facility, after transfer was
performed at the same time (data not shown).
Statistical analysis
Statistical significance was assessed by the paired two-tailed Student t test, and p < 0.05 was considered to be significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E-deficient mice
To evaluate the impact of E
deficiency on the overall development and life span of mice, wild-type
(E+/+), heterozygous
(E+/-),and
homozygous-deficient (E-/-)
mice on the 129/Sv x BALB/c background were monitored at weekly
intervals until senescence. Surprisingly, spontaneous inflammatory skin
lesions were observed in this cohort of
E-/- mice at 6 mo after
birth, and almost all animals >9 mo old were affected (16/18; 88.9%).
Heterozygous mice were affected with an intermediate frequency (4/30;
13.3%), consistent with their expression of reduced
E7 levels on T
lymphocytes (3), and wild-type mice were not affected
(0/8; 0.0%) (Fig, 1a). The
inflammatory skin lesions were most commonly seen on the eyelids, but
were also observed on trunk and tail, and were manifested by chronic
inflammation resulting in ulceration in some cases (Fig. 1
a). The course of these lesions was variable, as some
lesions spontaneously resolved over time, whereas others worsened.
Spontaneous skin lesions developed independently in mice kept in two
different animal facilities. When the
E-deficient mice were further backcrossed to
the BALB/c strain and housed in the second animal facility, skin
lesions also occurred in some wild-type mice and were not clearly
correlated with E genotype. Thus, modifying
factors besides E7
contributed to the development of the skin lesions. Indeed, one such
factor may be environment.
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b, left panel), but subclinical skin lesions in
100% of E-/- mice (10/10
mice, 13–25 mo of age (mean, 18 mo), including two mice without
macroscopic lesions; Fig. 1b, middle and
right panels). Within the subclinical lesions, a dense mixed
leukocytic infiltrate was noted, composed of lymphocytes and
granulocytes (Fig. 1, b and c). Although few
CD8+ T cells were found in these lesions, there
were abundant CD4+ T cells both within the dermal
and the epidermal compartment, some of which expressed the activation
marker CD25 (high-affinity IL-2R -chain) (Fig. 2a). Epidermal changes
included marked acanthosis (increase of viable cell layers) and
moderate ortho-hyperkeratosis (thickening of the stratum corneum) (Fig. 1b), de novo expression of ICAM-1 and MHC class II by
keratinocytes, and suprabasal expression of integrin
6 (Fig. 2b). In addition, there was
an increase in number and size of dermal blood vessels (Figs. 1b and 2b). In clinically apparent lesions,
ulcers were surrounded by a marked reactive epidermal hyperplasia and
contained a dense infiltrate of lymphocytes and neutrophils (Fig. 1c). In comparison with uninvolved skin, expression of
IFN-, GM-CSF, IL-6, IL-4 (Fig. 2c), IL-1, and
TNF- (data not shown) was increased dramatically in the skin
lesions of E-/- mice,
suggesting a mixed Th1/Th2 response.
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E-/- mice as compared with
the colonization observed in normal-appearing skin from either
E+/+ or
E-/- mice. In addition,
bacterial and fungal blood cultures were sterile, and the culture of
inflamed skin or eyelids and of nasopharyngeal washes revealed only
commensual organisms, which were similar in
E+/+ and
E-/- mice. Finally, viral
and bacterial serology were negative in
E+/+ and
E-/- mice, which have been
demonstrated to have normal levels of Igs and Ig isotypes
(3). Thus, there was no apparent infectious pathogen to
account for these lesions, leading us to consider whether the lesions
were autoimmune in pathogenesis.
Induction of inflammatory skin lesions in scid/scid
mice through adoptive transfer of E-deficient T
lymphocytes
To further evaluate the cutaneous lesions resulting from
E deficiency, adoptive lymphocyte transfer
studies were performed into MHC-matched scid/scid mice. In
these studies, recipient mice that had been reconstituted with
1.7–2 x 107
E+/+ splenic leukocytes
appeared to be normal and healthy and did not develop cutaneous lesions
during the 6-wk observation period. In contrast, 100% of mice
reconstituted with splenocytes from
E-/- donors developed
inflammatory skin lesions associated with a 50–60% increase in ear
thickness (0.438 mm (n = 3, SD = 0.019) in
recipients of E-deficient donor cells vs 0.285
mm (n = 3, SD = 0.005) in recipients of wild-type
cells, p = 0.007). This was especially apparent on the
ears (data not shown), feet, and surrounding the eyes (Fig. 3). These lesions were characterized by
an infiltration of leukocytes, including
CD3+/CD4+ T cells (which
were presumed to be donor cells, since scid/scid recipients
have very few CD3+ T cells) and neutrophils.
Epidermal changes included acanthosis and hyperkeratosis (Fig. 3b) and ulcer formation in 30% of the recipients (one of
three animals in each of two independent experiments). Similar to the
spontaneous lesions in E-deficient mice, very
few CD8+ T cells were present within the
inflammatory lesions in scid/scid recipients reconstituted
with E-deficient splenocytes (Fig. 3b), suggesting a primary pathogenic role of
CD4+ E-deficient T
cells. The inflammatory skin lesions in scid/scid mice first
were observed 2 wk after adoptive transfer and persisted during the
6-wk observation period (Fig. 3c). Although ulcers did not
develop consistently and the skin was more diffusely involved, the
cutaneous inflammation in mice reconstituted with
E-/- splenocytes was
reminiscent of the spontaneous lesions in aging
E-/- mice. Thus, transfer
of spleen-derived leukocytes from E-deficient
mice into MHC-matched scid/scid mice initiated skin lesions
in immunodeficient recipients appeared to be induced
by CD4+, but not
CD8+ T cells. This hypothesis was supported by an
additional adoptive transfer in which inflammatory skin alterations
were observed similarly in mice reconstituted with
E-deficient unfractionated splenocytes,
purified T cells, or purified CD4+ T cells, but
not in recipients of CD8+ T cells
(n = 3 in each group, data not shown).
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E7 is involved in the
generation of murine hyperproliferative inflammatory skin lesions
To further test the hypothesis that
E7 is involved in the
pathogenesis of hyperproliferative inflammatory skin alterations, a T
cell-mediated mouse model of a psoriasiform skin disorder was used
(18). In this system, transfer of MHC-matched but minor
histocompatibility-mismatched
E+/+
CD4+/CD45RBhigh donor cells
induced psoriasiform skin inflammation in scid/scid mice in
addition to the intestinal inflammation that is known to follow
transfer of syngeneic
CD4+/CD45RBhigh donor cells
(19, 20). This inflammatory skin disease model is
environmentally influenced. Within the murine psoriasiform lesions,
epidermal T cells expressed
E7
(Fig. 4a). To determine whether the
E7 integrin was
involved in the pathogenesis of the murine hyperproliferative
inflammatory skin disorder, the development of these lesions was
compared in scid/scid mice reconstituted with
CD4+/CD45RBhigh T cells
derived from wild-type or E-deficient mice. In
both cases, abundant CD3+ donor T cells
infiltrated the skin of the recipients. As expected, there was
prominent expression of
E7 on epidermal T
cells in recipients of wild-type
CD4+/CD45RBhigh donor
cells, but not in recipients of E-deficient
donor cells (Fig. 4a). Interestingly, the psoriasiform skin
inflammation was worsened significantly when
E-/- donor cells were used,
as assessed by both clinical score and ear thickness (Fig. 4, b and c). In addition, in vivo BrdU incorporation
in epidermal keratinocytes was 44% higher in recipients of
E-/- donor cells as
compared with recipients of wild-type cells, indicating stronger
hyperproliferation (288 BrdU+ cells/mm (±20.89)
vs 200.1 (±23.03), n = 3, Fig. 4d). These
findings suggest that E deficiency on the
donor cells worsened the disorder induced by
CD4+/CD45RBhigh T cells.
However, it is also possible that E deficiency
induced skin changes that were superimposed upon the psoriasiform
alterations that result from T cell transfer.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E-deficient mice developed inflammatory skin
lesions, apparently due to an aberrant immune reaction, as transfer of
T cells from E-/- mice
induced a similar phenotype in scid/scid recipients.
Integrin E7
expression has been observed on some epidermal T cell malignancies
(4, 15, 24) and on T lymphocytes in some benign skin
conditions (16, 17). However, it is not generally thought
to play an important role in the localization or function of cutaneous
T cells. Thus, our observation was surprising and suggests a broader
role of the E7
integrin than had been previously appreciated. As E-cadherin, the known
E7 counterreceptor
(1, 2), is constitutively expressed within the epidermis
(25), it is likely that
E7 expressed on
cutaneous T cells binds to its ligand there. This interaction may serve
to enhance the immigration or retention of
E7+
cutaneous T cells in the epidermis. This would be consistent with the
expression of E7 on a
greater proportion of the epidermal T cells than of the dermal T cells
in cutaneous lesions. The adhesive functions of
E7 on cutaneous T
cells are likely to be mediated in the context of other adhesive
molecules. These might include the binding of
1 integrins, LFA-1, or as yet unknown
molecules on cutaneous T cells with ICAM-1 or the newly identified
lymphocyte endothelial epithelial cell adhesion molecule (LEEP-CAM) on
keratinocytes (26, 27, 28, 29, 30). In addition, it has been suggested
that there is another ligand for
E7 on keratinocytes
that has not yet been identified at the molecular level, which could be
important in keratinocyte interactions with
E7+
leukocytes (31).
The E7–E-cadherin
interaction could also result in outside-in signaling in response to
ligand binding by either
E7 on T cells or
E-cadherin on epithelial cells. Specifically, a role for
E7 in signaling has
been indicated by evidence that
anti-E7 mAbs
enhance the proliferation of T lymphocytes in response to suboptimal
concentrations of anti-CD3 (7) and can induce the
lysis of target cells in vitro (6, 8). In addition,
E-cadherin is known to transmit signals that are important in
regulating epithelial cell functions (32, 33, 34). Thus,
intracellular signals induced by
E7/E-cadherin binding
in either T cells or epidermal keratinocytes could modulate the
cytokine responses or differentiation, proliferation, or survival of
either cell type. Consistent with this possibility, the presence of
E7+
T lymphocytes adjacent to acinar epithelial cells has been found to
correlate with epithelial cell apoptosis in tissue samples derived from
Sjögren’s syndrome patients (35).
Interestingly, integrin E deficiency also
worsened murine psoriasis-like skin lesions induced by
CD4+/CD45RBhigh T
lymphocytes in environmental conditions that were permissive for lesion
development. This was in contrast to the observation that
E deficiency alleviated intestinal
inflammation that occurred concomitantly in these mice (M.P.S., J.P.D.,
and C.M.P., unpublished observations). There are several potential
mechanisms by which E deficiency could modify
the phenotypic outcome of partial immune reconstitution in
immunodeficient mice. First, the lack of E
expression might prevent some T cell subsets from localizing to the
intestinal epithelium. These cells might then be shunted to the skin,
where they would induce inflammation due to their production of
inflammatory cytokines (36). In addition,
E deficiency could result in the loss of a
regulatory signal transmitted through the
E7 integrin that
modulates T cell responses. Such signaling might modify the response of
cutaneous T cells to stimulation, and thereby result in T cell
dysregulation in the skin under conditions in which the T cells become
activated.
Overall, our results demonstrate a novel and unexpected function of the
E7 integrin within
the cutaneous immune system. These studies also suggest that
E deficiency may be a genetic factor
predisposing to inflammatory skin disease under some environmental
conditions and/or in the context of other genetic factors, based upon
the presence of inflammatory skin lesions in
E-/- mice. This possibility
is supported by the observation that hyperproliferative inflammatory
skin lesions in a murine model of psoriasis were exacerbated when the
transferred T cells lacked E expression.
Additional genetic studies will be required to determine whether
E deficiency is associated with an increased
risk of inflammatory skin disease in humans, as it appears to be in
mice, and to identify the role of
E7 in cutaneous T
lymphocyte responses during antigenic or autoimmune responses.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Christina M. Parker, Brigham and Women’s Hospital, Smith Building, Room 552B, 1 Jimmy Fund Way, Boston, MA 02115.
3 Abbreviation used in this paper: BrdU, 5-bromo-2'-deoxyuridine; ABC, avidin-biotin complex.
Received for publication March 29, 2000. Accepted for publication August 29, 2000.
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E7 integrin. Nature 372:190.[Medline]
M2907 (E7). Eur. J. Immunol. 25:852.[Medline]
E (CD103)-deficient mice. J. Immunol. 162:6641.M2907 by a major subpopulation of dendritic cells in mice. Eur. J. Immunol. 23:3365.[Medline]
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E7 with E-cadherin. J. Cell Biol. 140:197.E7 integrin in cutaneous T cell lymphoma. Am. J. Pathol. 145:1148.[Abstract]
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E7 on skin-infiltrating T cells. J. Allergy Clin. Immunol. 100:694.[Medline]
, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J. Immunol. 162:7480.E7 integrin (CD103) and E-cadherin in epidermotropism in cutaneous T-cell lymphoma. J. Cutan. Pathol. 23:312.[Medline]
1 integrins in epidermotropism of malignant T cells. Am. J. Pathol. 141:855.[Abstract]
E7-positive lymphocytes to oral and skin keratinocytes. Immunology 98:9.[Medline]
E7+ T cells around acinar epithelial cells with apoptosis in patients with Sjögren’s syndrome. J. Immunol. 163:2226.This article has been cited by other articles:
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K. Uraushihara, T. Kanai, K. Ko, T. Totsuka, S. Makita, R. Iiyama, T. Nakamura, and M. Watanabe Regulation of Murine Inflammatory Bowel Disease by CD25+ and CD25- CD4+ Glucocorticoid-Induced TNF Receptor Family-Related Gene+ Regulatory T Cells J. Immunol., July 15, 2003; 171(2): 708 - 716. [Abstract] [Full Text] [PDF]
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 P. J. Kilshaw and J. M.G. Higgins Alpha E: No More Rejection? J. Exp. Med., October 7, 2002; 196(7): 873 - 875. [Full Text] [PDF]
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 J. Lehmann, J. Huehn, M. de la Rosa, F. Maszyna, U. Kretschmer, V. Krenn, M. Brunner, A. Scheffold, and A. Hamann Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25- regulatory T cells PNAS, October 1, 2002; 99(20): 13031 - 13036. [Abstract] [Full Text] [PDF]
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D. Zelenika, E. Adams, S. Humm, L. Graca, S. Thompson, S. P. Cobbold, and H. Waldmann Regulatory T Cells Overexpress a Subset of Th2 Gene Transcripts J. Immunol., February 1, 2002; 168(3): 1069 - 1079. [Abstract] [Full Text] [PDF]
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 S. Kutlesa, J. T. Wessels, A. Speiser, I. Steiert, C. A. Muller, and G. Klein E-cadherin-mediated interactions of thymic epithelial cells with CD103+ thymocytes lead to enhanced thymocyte cell proliferation J. Cell Sci., January 12, 2002; 115(23): 4505 - 4515. [Abstract] [Full Text] [PDF]
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 L. Stevceva, B. Kelsall, J. Nacsa, M. Moniuszko, Z. Hel, E. Tryniszewska, and G. Franchini Cervicovaginal Lamina Propria Lymphocytes: Phenotypic Characterization and Their Importance in Cytotoxic T-Lymphocyte Responses to Simian Immunodeficiency Virus SIVmac251 J. Virol., January 1, 2002; 76(1): 9 - 18. [Abstract] [Full Text] [PDF]
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 E. Corps, C. Carter, P. Karecla, T. Ahrens, P. Evans, and P. Kilshaw Recognition of E-cadherin by Integrin alpha Ebeta 7. REQUIREMENT FOR CADHERIN DIMERIZATION AND IMPLICATIONS FOR CADHERIN AND INTEGRIN FUNCTION J. Biol. Chem., August 10, 2001; 276(33): 30862 - 30870. [Abstract] [Full Text] [PDF]
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), 
), or a
mixture of both donor cell types (•). Ear thickness of the recipients
was monitored as parameter of skin inflammation. This experiment is one
representative experiment of two performed that showed similar results
(n = 3 per group).