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Prepublished online as a Blood First Edition Paper on September 26, 2002; DOI 10.1182/blood-2002-05-1586.
 Previous Article | Table of Contents | Next Article 
Blood, 1 February 2003, Vol. 101, No. 3, pp. 801-806
CHEMOKINES
Endothelial induction of the T-cell chemokine CCL21 in T-cell
autoimmune diseases
Kent W. Christopherson II,
Antoinette F. Hood,
Jeffrey B. Travers,
Heather Ramsey, and
Robert A. Hromas
From the Department of Microbiology and Immunology and
the Walther Oncology Center, Department of Dermatology and the Wells
Center for Pediatric Research, Division of Hematology/Oncology and
Walther Oncology Center, Indiana University Medical Center,
Indianapolis.
 |
Abstract |
The signals that mediate T-cell infiltration during T-cell
autoimmune diseases are poorly understood. The chemokine CCL21 (originally isolated by us and others as
Exodus-2/6Ckine/SLC/TCA4) is highly potent and highly specific
for stimulating T-cell migration. However, it is thought to be
expressed only in secondary lymphoid organs, directing naive T cells to
areas of antigen presentation. It is not thought to play a role in
T-cell effector function during a normal immune response. In this study
we tested the expression of T-cell chemokines and their receptors
during T-cell autoimmune infiltrative skin diseases. By using
immunohistology it was found that the expression of CCL21 but not CCL19
or 20 was highly induced in endothelial cells of T-cell autoimmune
diseases. The receptor for CCL21, CCR7, was also found to be highly
expressed on the infiltrating T cells, most of which expressed the
memory CD45Ro phenotype. These data imply that the usual loss of CCL21
responsiveness in the normal development of memory T-cell effector
function does not hold for autoimmune skin diseases.
(Blood. 2003;101:801-806)
© 2003 by The American Society of Hematology.
| |
Introduction |
Chemokines are a family of structurally related
proteins that are the major mediators of all leukocyte
migration.1-4 There are many reports that chemokines or
their receptors are important in human disease.1-4 They
play crucial roles in many diseases that have inflammatory tissue
destruction, such as adult respiratory distress syndrome, myocardial
infarction, rheumatoid arthritis, and atherosclerosis.1-7
Chemokines are also potent inhibitors of
hematopoiesis.8-10 We and others isolated a novel CC
chemokine termed CCL21 (originally Exodus-2/SLC/6Ckine/TCA4)
that is the most powerful chemoattractant for T cells yet
defined.10-12 CCL21 also attracts B cells and natural
killer (NK) cells, although not to as great an extent as T
cells.10-12 It does not chemoattract monocytes or
granulocytes.10-13
CCL21 also plays an important role in T-cell adhesion. T-cell
trafficking from the vasculature to tissue sites of inflammation or
disease is mediated by a defined series of steps.14,15
First, T cells initially tether and roll along the endothelium via
L-selectin. Three chemokines, CXCL12, CCL19, and CCL21, can then
mediate a firm adherence to endothelial intercellular adhesion
molecule-1 (ICAM-1) by stimulating the T-cell integrin
lymphocyte function antigen-1 (LFA-1). Adherent cells then follow a
chemotactic gradient into inflamed tissue. Because CCL21 is strongly
expressed in high endothelial venules of lymph nodes, it was thought
that it might mediate T-cell trafficking though secondary
lymphoid organs.14,15
This hypothesis was later found to be true. Homozygous deletion of the
receptor for CCL21, CCR7, found that mice without this receptor were
unable to both organize secondary lymphoid organs and mount a normal
immune response.13 Other studies have found that effector
memory T cells infiltrating inflamed/infected tissues in a normal
immune response lacked expression of CCR7.16,17 Thus, it
has been hypothesized that the CCL21/CCR7 axis is essential for
appropriate naive T-cell migration to secondary lymphoid organs for
antigen presentation, but that this axis is not required for effector
memory T cells (postantigen exposure) to migrate toward and respond to
the inflammatory stimuli.16,17
It has been thought that these effector memory T cells lacking CCR7 are
the major agents of T-cell tissue infiltration during inflammation.16,17 In this study we investigated whether
the expression of CCL21 implicated it in the pathogenesis of T-cell autoimmune diseases of the skin. Contrary to prevailing thought, we
found that CCL21 is highly induced in the endothelium of T-cell autoimmune diseases but not in normal tissue. The receptor for CCL21,
CCR7, was also highly expressed on these infiltrating T cells, most of
which were of the CD45Ro memory phenotype. Thus, the migration of the
effector memory T cells in these autoimmune diseases was likely
regulated by CCL21.
| |
Patients, materials, and methods |
The skin diseases studied were the autoimmune diseases atopic
dermatitis and lichen planus, and the related T-cell infiltrative skin
disease graft-versus-host disease (GVHD). Skin biopsies were obtained
after Indiana University institutional review board-approved informed consent on patients with these T-cell infiltrative diseases of
the skin. Immunohistology was chosen as an assay of protein expression
because it allows morphologic identification of the cell type
expressing the protein being investigated. Biotinylated antibodies
against human CCL19 (previously ELC/MIP-3beta/Exodus-3), CCL20
(previously LARC/MIP-3alpha/Exodus-1), CCL21, CCR7, and CD45Ra were
purchased from R&D Systems (Minneapolis, MN) or from BD Pharmingen (San
Diego, CA). Nonbiotinylated antibodies against CD45Ro and appropriate
secondary biotinylated antibodies were purchased from BD Pharmingen.
Immunohistology of paraffin-imbedded specimens was performed
essentially as we previously described,18 with the
exception that the strep-avidin peroxidase reaction was performed
directly on the primary antibodies for those antibodies that were
biotinylated. Biotin-avidin/peroxidase/diaminobenzidine (DAB)
staining was used to develop the signal (Vectastain Elite ABC Kit and
DAB Substrate Kit; Vector Labs, Burlingame, CA). Slides were
counterstained with Hematoxylin Nuclear Counterstain (Vector Labs).
Three patient skin samples were tested for each disease, and 3 individuals for healthy skin served as controls. All samples showed
identical results to those shown in the photomicrographs here.
| |
Results |
Immunohistology was used to analyze the expression
pattern of potent and specific T-cell chemokines in immunologic skin
diseases in which T-cell infiltration mediates the pathology. Healthy
skin was used as a control. Immunohistologic analysis found that
healthy skin did not express CCL19 protein in any cell type (Figure
1A). None of the cases of GVHD and lichen
planus expressed CCL19 in any cell type (Figure 1C-D). However, one
case of atopic dermatitis of the 3 analyzed expressed CCL19 in
macrophages and dendritic cells (Figure 1B). CCL20 was constitutively
expressed in basal keratinocytes and macrophages of healthy and
diseased skin (Figure 1E-H). Most lymphocytes in healthy or diseased
skin did not express CCL20. Thus, the expression of CCL20 did not
change in any of the skin diseases as compared with healthy
skin.
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| Figure 1.
Immunohistologic analysis of the expression of CCL19 and CCL20
in healthy and T-cell infiltrative skin diseases.
The antibody-specific peroxidase reaction is stained brown; the
hematoxylin nuclear counterstain is blue. All photomicrographs are at
× 50 original magnification. (A) CCL19 expression in healthy
skin. (B) CCL19 in atopic dermatitis. (C) CCL19 in lichen
planus. (D) CCL19 in GVHD. One of the 3 skin samples of atopic
dermatitis had expression of CCL19 in dendritic cells, which is shown
in panel B. (E) CCL20 expression in healthy skin keratinocytes
(right) and macrophages (left). (F) CCL20 expression in atopic
dermatitis, (G) CCL20 expression in lichen planus, and (H) CCL20
expression in GVHD. There was no distinction in CCL20 expression
between healthy and diseased skin. Three separate patient samples were
tested for healthy and 3 for diseased
skin.
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Healthy skin did not express any CCL21 protein (Figure
2A). However, the expression of CCL21 was
induced in dermal endothelial cells in all 3 T-cell skin diseases,
atopic dermatitis, lichen planus, and GVHD (Figure 2B-D). The
endothelial cells expressing CCL21 protein in all of the
photomicrographs shown were in venules, as no smooth muscle cells are
seen in these vessels. In addition, the expression of CCL21 was not
just in a few selective venules but was in most of the venules seen in
all biopsies. Note the lymphocyte adhering to the endothelium of the
venule shown in GVHD (Figure 2D). When a venule expressed CCL21, that
expression was generally circumferential and ubiquitous in all
endothelial cells seen in that venule.
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| Figure 2.
Immunohistologic analysis of the expression of CCL21 and CCR7 in
healthy skin and T-cell autoimmune skin disease.
CCL21 is not expressed in samples of healthy skin (A) but is
expressed in venule endothelial cells of atopic dermatitis (B), lichen
planus (C), and graft-versus-host disease by immunohistology (D). (E)
CCR7 expression in healthy skin. (F) CCR7 expression in atopic
dermatitis. (G) CCR7 expression in lichen planus. (H) CCR7 expression
in GVHD. Three distinct patient skin samples were tested for each
disease and 3 for healthy skin. All showed results identical to those
shown here. Lower power views of the autoimmune samples found that all
venule endothelial cells express CCL21. The photomicrographs
shown here are representative of all samples. All slides were
photographed at × 50 original magnification.
|
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Next, the expression of CCR7, the receptor for CCL21, on lymphocytes in
healthy and autoimmune skin diseases was assessed. CCR7 was expressed
in only a few lymphocytes in healthy skin biopsies (Figure 2E).
However, as seen in Figure 2F-H, most of the lymphocytes in all 3 autoimmune skin diseases, atopic dermatitis, lichen planus, and GVHD,
highly express CCR7. Interestingly, there are also dendritic cells that
express CCR7 that are present in the diseased skin.
Given the previously described hypothesis of T-cell function in an
immune response, in which the effector memory T cells have lost CCR7
expression and CCL21 responsiveness, this raised the question of
whether the T cells infiltrating the skin of these autoimmune diseases
had a naive (preantigen exposure) or memory (postantigen) phenotype.
CD45Ra is a surface marker of naive T cells and CD45Ro is a marker of
memory T cells. The expression of these markers on the
skin-infiltrating T cells was tested by using immunohistology as
before. As shown in Figure 3A-D, T cells in healthy or autoimmune skin expressed CD45Ra, the marker for naive T
cells, in rare lymphocytes. In contrast, however, the marker for memory
T cells, CD45Ro, was highly expressed in most of the T cells in both
healthy skin and the autoimmune-diseased skin (Figure 3E-H).
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| Figure 3.
Immunohistologic analysis of the expression of CD45Ra and CD45Ro in
healthy skin and autoimmune skin disease.
(A) CD45Ra is poorly expressed in cells of healthy skin. CD45Ra is also
poorly expressed in rare lymphocytes in skin samples from patients with
T-cell autoimmune diseases: atopic dermatitis (B), lichen
planus (C), and graft-versus-host disease (D). However, most of the
skin-infiltrating lymphocytes in both healthy and diseased skin are
CD45Ra+. (E) CD45Ro is significantly expressed in samples
of healthy skin. Also, CD45Ro is highly expressed in skin samples from
patients with T-cell autoimmune diseases: atopic dermatitis
(F), lichen planus (G), and GVHD (H). The same 3 distinct
patient skin samples were tested for each disease, and the same 3 for
healthy skin as in the other figures. There was no difference
between the samples displayed here and those not shown. All slides were
photographed at × 50 original magnification.
|
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| |
Discussion |
The T-cell chemokine CCL19 is rarely expressed in any cells in
either healthy or diseased skin. One case of 3 of atopic dermatitis had
induced expression of CCL19 in macrophages and dendritic cells. However, because that induction was not consistently seen in all cases
of that skin disease, it is difficult to ascribe significance to it.
Further investigation will be needed to identify whether CCL19
expression in those T-cell-infiltrative skin diseases is a prognostic
factor. It is possible that CCL19 macrophage expression changes the
biology of the disease, and those individual cases have distinct
clinical behaviors.
CCL20 is expressed constitutively in keratinocytes and macrophages in
both healthy and diseased skin. Because CCL20 expression did not change
with the initiation of clinical T-cell-infiltrating skin disease, it
is less likely that it plays a role in initiating or maintaining the
disease pathology.
In contrast, CCL21 expression is consistently induced in the
endothelial cells of all T-cell infiltrative autoimmune diseases of the
skin that were tested. No other T-cell chemokine was consistently induced in T-cell-infiltrative skin diseases. The endothelial expression of CCl21 was specifically induced in those T-cell skin diseases; it is not expressed in the endothelial cells of healthy skin.
In addition, most lymphocytes present in those autoimmune skin samples
were CCR7+. This finding shows that the CCL21-CCR7 axis is
highly induced in these T-cell infiltrative skin diseases. Because
CCL21 is the most potent and specific T-cell chemokine, this raises the
intriguing question of whether its induction mediates the aberrant
T-cell infiltration of the skin in these diseases.
Although the studies here clearly indicate that CCL21 is overexpressed
in these T-cell-mediated skin diseases, it is not clear whether such
overexpression is important in initiating or rather maintaining the
skin pathology. Is CCL21 expressed as a result of the disease, or does
its expression produce the disease? It is clinically difficult to
obtain biopsies just prior to a disease flare. All of the specimens
here were obtained during clinically obvious skin pathology. All
biopsies were obtained, however, at the initial time of diagnosis.
Therefore, this question may require animal models to answer. It is
also quite possible that CCL21 is important in both initiation (via
early recruitment of self-presenting dendritic cells) and maintenance
(via T-cell chemotaxis) of these diseases. No matter what the time
course is, such abnormal expression of CCL21 will still result in
increased T-cell adhesion and chemotaxis at sites of its expression,
the pathologic hallmark of these diseases.
Most of the T cells in both healthy and autoimmune skin did not express
CD45Ra, a marker of naive T cells, but highly expressed CD45Ro, a
marker of memory T cells. Thus, a model can be hypothesized from these
data here. In these T-cell diseases, CCL21 is induced in the
endothelium of the target organ, the skin, stimulating the
transmigration of CCR7+/CD45Ro+ T cells that
are reactive to autologous antigens. These findings raise 2 possible
steps that may be required for the skin pathology in these T-cell
diseases. First, the induction of endothelial CCL21 may be important to
stimulate responsive T-cell transmigration. Second, the maintenance of
CCR7 in these autoreactive memory CD45Ro+ T cells would be
required for this abnormal migratory response. These 2 abnormalities
may underlie the pathology of this abnormal immune response.
This marked induction of CCL21 in the venule endothelial cells and the
abundant presence of CCR7+/CD45Ro+ T cells in
T-cell infiltrative skin diseases appears contradictory to the recent
model describing effector memory T cells as lacking CCR7 and being
unresponsive to CCL21.16,17 Those reports investigated models of the normal T-cell immune response, whereas the diseases studied here are autoimmune in origin and do not represent a normal T-cell immune response. Therefore, it is still possible that in the
normal immune response to injury or infection CCL21 plays a little role
in the tissue infiltration of effector memory T cells. Indeed, as
mentioned earlier, the abnormal induction of CCL21 and the maintenance
of CCR7 may lie at the heart of the pathology of the autoimmunity in
the diseases studied here. However, the data here clearly indicate that
the memory T cells producing this aberrant immune effect express CCR7
and, therefore, could respond to the CCL21 induced on the endothelial
cells with transmigration into the target tissues.
Macrophages and dendritic cells were also found to express CCR7 in
biopsy specimens of the T-cell autoimmune skin diseases studied here.
This finding implies that the abnormal endothelial expression of CCL21
in these autoimmune diseases recruited antigen-presenting cells to
inflamed skin. Figure 2C shows a dendritic cell with a large number of
lymphocytes adhering to it, providing evidence that at least physical
association between antigen-presenting cells and potential lymphocyte
responders occurs in the diseased skin.
There are a number of other autoimmune diseases whose pathology relies
on aberrant T-cell infiltration, such as rheumatoid arthritis and
inflammatory bowel disease. It is possible that the aberrant expression
of CCL21/CCR7 may also be present in these diseases. This raises the
possibility that the endothelial regulation of T-cell migration could
be targeted for therapy of these and other T-cell infiltrative
diseases. Agents that interfere with the abnormal recruitment of T
cells from the circulation to sites of pathologic inflammation by
endothelial cells expressing CCL21 may be effective in treating these
diseases. Blocking T-cell transmigration from the blood to the target
tissues may at least decrease the pathologic damage of these tissues by
cytotoxic T cells. Therefore, this study also implies that CCL21 may be
an important pharmacologic target in T-cell autoimmune diseases.
Basal keratinocytes constitutively produce CCL27, a CC chemokine that
we and others isolated, that chemoattracts CLA+ T cells to
the skin.19,20 This chemokine also plays a role in
stimulating T-cell infiltration of the skin in allergen-mediated skin
diseases, as antibody neutralization of CCL27 suppresses lymphocyte
recruitment to the skin in a mouse model of allergic dermatitis.20 The constitutive expression of CCL27 is
probably important for T-cell infiltration of the skin in human
autoimmune skin diseases. However, because CCL27 is also expressed in
healthy skin and is not induced in the disease state like CCL21, it may not be the initiating step in the abnormal T-cell infiltration seen in
these autoimmune diseases.
There are 2 other studies that lend credence to our hypothesis that the
CCL21/CCR7 axis is critical for autoimmune T-cell skin infiltration.
First, ectopic expression of CCL21 in the pancreas was sufficient to
recruit abundant lymphocytes to this nonlymphoid tissue.21
Thus, CCL21 expression alone can mediate abnormal T-cell tissue
infiltration. Secondly, it has been reported that CCL21 is essential
for the homeostatic proliferation of CD4+ T cells in
lymphopenic hosts.22 When there is a decreased number of
CD4+ T cells and CCL21 is not expressed, T cells cannot
proliferate to homeostatically increase T-cell number. More germane to
the data here, that study found that transferring antigen-specific CD4+ T cells to antigen-expressing hosts that had
pancreatic expression of CCL21 induced an autoimmune disease in that
organ.22 Thus, that study indicates that the aberrant
induction of CCL21, such as is seen here, could induce tissue-specific
autoimmune T-cell infiltration, given the appropriate antigenic circumstance.
In summary, the abnormal induction of endothelial CCL21 and the
recruitment of CCR7+/CD45Ro+ T cells to target
tissues may be a novel and significant pathway in tissue damage in some
autoimmune diseases. The mechanism of this abnormal induction of CCL21
and the maintenance of CCR7 on CD45Ro T cells to enable them to respond
to this abnormal CCL21 expression may lie at the center of the
molecular pathology of these diseases. It also indicates that a
modification of the effector memory hypothesis of T-cell trafficking
and function needs to be made for autoimmune diseases. Finally, these
data imply that CCL21/CCR7 may be a novel and beneficial target of
therapy in these diseases.
| |
Footnotes |
Submitted May 29, 2002; accepted September 3, 2002.
Prepublished
online as Blood First Edition Paper, September 26, 2002; DOI
10.1182/blood-2002-05-1586.
Supported by grant RO1 HL66308 (R.A.H.) and RO1 HL629906
(J.B.T.) from the National Institutes of Health.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Robert A. Hromas, Division of
Hematology/Oncology and Walther Oncology Center, R4-202, Indiana
University Medical Center, 1044 W Walnut St, Indianapolis, IN 46202;
e-mail: rhromas{at}iupui.edu.
| |
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W. Weninger, H. S. Carlsen, M. Goodarzi, F. Moazed, M. A. Crowley, E. S. Baekkevold, L. L. Cavanagh, and U. H. von Andrian
Naive T Cell Recruitment to Nonlymphoid Tissues: A Role for Endothelium-Expressed CC Chemokine Ligand 21 in Autoimmune Disease and Lymphoid Neogenesis
J. Immunol.,
May 1, 2003;
170(9):
4638 - 4648.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction