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Regular Articles |
From the Laboratory of Immunology and Vascular Biology,*
Department of Pathology, the Department of Microbiology and
Immunology,
the Department of
Surgery,¶
and the Division of Immunology and
Rheumatology,||
Stanford University School of Medicine,
Stanford, California; Center for Molecular Biology and
Medicine,
Veterans Affairs Palo Alto Health
Care System, Palo Alto, California; Millennium Pharmaceuticals,
Inc.,
Cambridge, Massachusetts; Division of
Respiratory Medicine,**
Institute for Lung
Health, Leicester University Medical School, Leicester, United Kingdom;
and the Joint Program in Transfusion
Medicine,
Children’s Hospital,
and the Department of Pathology, Harvard Medical School,
Boston, Massachusetts
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Abstract |
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4ß7 expression. CCR4 was expressed at high
levels by skin-infiltrating lymphocytes, at lower levels by
lung and synovial fluid lymphocytes, but never by intestinal
lymphocytes. Only the high CCR4 levels characteristic of skin
lymphocytes were associated with robust chemotactic and adhesive
responses to TARC, consistent with a selective role for CCR4 in
skin lymphocyte homing. In contrast, CXCR3 and CCR5 were
present on the majority of lymphocytes from each non-lymphoid tissue
examined, suggesting that these receptors are unlikely to
determine tissue specificity, but rather, may play a
wider role in tissue inflammation.
The clearest evidence to support the concept of tissue-dedicated
trafficking of peripheral blood lymphocyte subsets exists at the level
of their expression of adhesion molecules.1,2
Circulating
lymphocytes associated with skin homing express the E-selectin ligand
CLA (cutaneous lymphocyte antigen), whereas those associated with
homing to the gastrointestinal tract express the MAdCAM-1 ligand
4ß7 integrin. Although
skin- and intestinal-specific lymphocyte populations are the best
studied, there is reason to believe that additional populations
dedicated to other tissues may exist.1,2
In addition to differential expression of adhesion molecules, differential expression of chemokine receptors may also contribute to tissue-specific homing. This hypothesis would predict the disproportionate expression of particular chemokine receptors by lymphocytes that have infiltrated tissues that express the corresponding chemokine ligand. We have recently found support for this prediction.4 By carefully isolating T cells from various human tissues, we demonstrated that the chemokine receptor CCR9 is highly expressed by nearly all T lymphocytes infiltrating the small intestine (the one organ outside of the thymus where the CCR9 ligand TECK is highly expressed). In contrast, CCR9 was not expressed by T lymphocytes isolated from other tissues tested, including skin, liver, synovium, and lung. In contrast to small intestine-derived lymphocytes, CCR9 was expressed by only a small percentage of colon lymphocytes, suggesting that circulating intestinal-specific lymphocytes may be further subdivided into small intestine-dedicated versus large intestine-dedicated populations.4
To further examine similarities and differences among lymphocytes that
have infiltrated diverse human tissues, we have investigated the
differential expression of three more chemokine receptors (CCR4, CCR5,
and CXCR3) by tissue-infiltrating lymphocytes. We previously reported
that circulating skin-associated CLA+ lymphocytes
uniformly express high levels of CCR45
and that the CCR4
ligand TARC6
is expressed on normal and inflamed cutaneous
(but not intestinal) endothelium. Taken together, these two findings
suggest that CCR4 and TARC may participate in skin-specific lymphocyte
recruitment.3,5
Interestingly, CCR4 monoclonal antibodies
(mAbs) also recognized a subset of
CLA-/4ß7-
peripheral blood memory CD4+
lymphocytes.5
The role of CCR4 here is unknown, but these
cells may represent another skin-associated subset or a subset
dedicated to a systemic tissue.
CCR5 and CXCR3 have been reported to be tissue-specific receptors in multiple organs. CCR5 is expressed by lymphocytes in intestinal tissues and was suggested to be a mucosa-specific receptor.7,8 However, other groups reported CCR5 expression on lymphocytes in the brains of multiple sclerosis patients,9 liver,10 and on synovial lymphocytes from arthritis patients.11,12 CXCR3 expression was similarly reported on intestinal,7 inflamed brain,9 liver,10 and synovial11,12 lymphocytes. Thus, the roles of CCR4, CCR5, and CXCR3 in tissue-specific lymphocyte homing require further clarification.
By identifying the similarities and differences in expression of chemokine receptors by lymphocytes that have infiltrated a variety of extralymphoid tissues, we hope to gain an understanding of the specialized CD4+ lymphocyte subsets involved in inflammation and immune surveillance in particular tissue sites. Such knowledge may identify pharmacological targets that could be used to manipulate tissue-specific homing or other chemokine-mediated inflammatory functions, making possible treatments for regional autoimmune diseases (eg, psoriasis or Crohn’s disease) as well as tailored treatments to prevent rejection of transplanted tissues.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionsReferences |
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Anti-human CCR4 mAbs 1G1 and 2B10 (both mouse
IgG1),5
CLA-FITC mAb HECA-452 (rat
IgM),13
and
4ß7-PE mAb Act-1
(mouse IgG1)14
have been previously described.
Unconjugated mouse anti-human CD45RO (IgG2a,
clone UCHL1), CCR5 (IgG2a, clone 2D7; known to
correlate best with genetic expression of CCR515
), CXCR3
(IgG1, clone 1C6), and directly conjugated mouse
anti-human CD45RA-FITC (IgG2b, clone HI100),
CD69-PE (IgG1, clone FN50), CD3-FITC
(IgG1, clone UCHT1), TCRß-FITC (IgM, clone
T10B9.1A-31), and CD4-APC (IgG1, clone RPAT4)
were obtained from PharMingen, Inc. (San Diego, CA). Recombinant human
SDF-1 and TARC were purchased from Peprotech (Rocky Hill, NJ).
ICAM-1 was purified from human tonsils as described.5
Tissue Sources and Lymphocyte Isolation
Human jejunum, ileum, colon, lung, tonsil, and inflamed liver were obtained from patients undergoing various surgical procedures. Synovial fluid (SF) was obtained from patients undergoing diagnostic arthrocentesis. Peripheral blood was collected in heparinized tubes from healthy donors. Bronchoalveolar lavage (BAL) fluid was obtained by optic bronchoscopy from healthy volunteers. Skin lymphocytes were obtained from suction blisters in sensitized volunteers. All human subject protocols were approved by the Institutional Review Boards at Stanford University or Leicester University.
Peripheral blood lymphocytes were isolated as described.5 Briefly, after dextran sedimentation and separation of the mononuclear fraction over Ficoll (Amersham Pharmacia Biotech, Piscataway, NJ), monocytes were removed by two 30 minute rounds of adherence to plastic culture flasks in an incubator. Tonsil lymphocytes were obtained by dispersal of fresh tonsils through a stainless steel mesh followed by incubation in a plastic flask to deplete adherent cells. Bronchoalveolar lavage subjects were premedicated with nebulized salbutamol, lightly sedated with midazolam and the upper airway was anesthetized with 2% lignocaine. 180 ml of normal saline were inserted through the bronchoscope into the middle lobe of the right lung and the lymphocyte-containing fluid was aspirated using gentle suction (fluid recovery was 20 to 46%). Lymphocytes from the epithelium and lamina propria of human intestine were isolated as described previously.16 Briefly, the epithelium and any resident lymphocytes were removed from the lamina propria by gentle stirring in the presence of 1 mmol/L EDTA. The epithelium-free lamina propria was then dispersed through wire mesh. Lymphocytes were isolated from inflamed human skin as described previously.17 Briefly, skin lymphocytes were isolated from the fluid drained from suction blisters raised over the site of an epidermal delayed-type hypersensitivity reaction (to poison oak leaves or Candida albicans extract) elicited in allergic volunteers. Lymphocytes were isolated from normal lung, inflamed liver, and inflamed synovial fluid as described.4 Briefly, lung lymphocytes were obtained by mincing the tissue with fine scissors and passing the supernatant through gauze; liver lymphocytes were obtained after mechanical dispersal of liver pieces followed by Ficoll separation, and synovial fluid mononuclear cells were isolated by Ficoll separation.
We performed confirmatory studies to investigate whether chemokine receptor expression on extracted lymphocytes might have been altered by the tissue-chelation procedure. In these parallel experiments, purified lymphocytes (from peripheral blood) were treated by chelation in exactly the same manner as the tissue samples. Donor-matched, untreated and treated lymphocytes were then stained with the same mAbs to chemokine receptors and adhesion molecules presented in the text. We found no staining differences between the treated and untreated cells (Kunkel and Campbell, unpublished findings).
Adhesion and Chemotaxis Assays
Chemotaxis assays were performed using 24-well Transwell plates
(Corning Costar, Cambridge, MA; 5 µm pores) in RPMI 1640 supplemented
with 0.5% bovine serum albumin for 2 hours in an incubator as
described.5
Migrated cells were stained with CD4-APC,
CD45RA-CyChrome, CLA-FITC, and 4ß7-PE to analyze T cell subsets
(Pharmingen). Chemokine-triggered adhesion assays were performed as
described.5
Briefly, sorted lymphocytes were allowed to
settle on glass slides coated with purified human ICAM-1 and stimulated
to adhere with chemokines, after which the slides were gently washed
and bound lymphocytes were fixed with gluteraldehyde and counted using
NIH Image software (version 1.62b).
FACS Analysis
Tissue or blood lymphocytes were stained and gated for the populations of interest using markers labeled with fluorescein isothyocyanate (FITC), phycoerythrim (PE), or allophycocyanin (APC). Unconjugated (or isotype-matched control mAbs) were detected using a biotinylated horse anti-mouse IgG secondary antibody (Vector Laboratories, Burlingame, CA) and streptavidin-PerCP (Pharmingen). In some experiments, blood lymphocytes were stained for CCR4 and CD45RO and sorted on a FACSVantage SE (Becton-Dickinson). Four-color flow cytometry was carried out on a FACSCalibur (Becton-Dickinson) using CellQuest software, version 3.1 (Becton-Dickinson).
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Results |
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In an attempt to more thoroughly understand the phenotype of
tissue-infiltrating CD4+ lymphocytes, we have
undertaken to gently isolate lymphocytes from surgical specimens for
direct examination. Our lymphocyte isolation techniques involved
chelation at 4°C as previously described.4
This
technique allowed us to avoid prolonged (potentially destructive)
exposure of lymphocytes to digestive enzymes at 37°C as entailed by
conventional protocols. We first examined the activation and
naive/memory status of tissue infiltrating cells.
CD4+ lymphocytes from non-lymphoid tissues (eg,
inflamed skin, normal jejunum, lung BAL fluid, and psoriatic arthritis
SF in Figure 1, C–F
) were overwhelmingly
of the memory phenotype (CD45RA-). This is a
dramatic enrichment of memory cells over their representation in blood,
where they usually comprise less than 50% of
CD4+ T cells (Figure 1A)
. In contrast,
CD4+ T cells isolated from tonsil (a
representative secondary lymphoid organ) maintained a naïve to
memory ratio similar to that of blood (Figure 1B)
. Both lymphoid and
non-lymphoid tissues contained large numbers of cells of activated
phenotype (as assessed by the activation marker CD69, Figure 1
).
Activated cells were exceedingly rare in the blood (Figure 1A)
.
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To further characterize the tissue-derived lymphocytes, we
examined their expression of the two best-studied adhesion molecules
associated with tissue-specific homing: CLA and
4ß7 integrin. CLA is a
ligand for E-selectin, which allows CLA+ cells to
interact with E-selectin in cutaneous venules.
CLA+ cells home preferentially to cutaneous sites
in vivo, and T cells specific for cutaneous antigens reside
within this population.18
The
4ß7 integrin is a
ligand for MAdCAM-1, which allows
4ß7+
cells to interact with MAdCAM-1+ intestinal
venules. 4ß7- memory
cells home preferentially to intestinal sites in
vivo,19
and cells specific for intestinal antigens
reside within this population.20
Memory CD4+ cells from blood contained a mixture
of CLA-expressing,
4ß7-expressing, and
other less-well studied subsets (Figure 1, A
; far right panel).
However, when we examined cells isolated directly from skin or from
jejunal lamina propria we found essentially pure
CLA+ or
4ß7+
populations, respectively (Figure 1, C and D
; far right panels). In
contrast, CD4+ populations from the lung or
tonsil, where these molecules are proposed to play little or no role in
homing, contained very few cells with high levels of these molecules
(Figure 1, B and E
; far right panels). Interestingly, lymphocytes from
the synovial fluid of autoimmune arthritis patients appeared to be an
exception to the rule of tissue-specific lymphocyte homing (eg,
psoriatic arthritis in Figure 1E
; far right panel). Although
naïve cells were excluded from this extra-lymphoid site, the
representation of memory cells expressing CLA or
4ß7 was similar to
that of blood.
Chemokine Receptor Expression of Tissue-Infiltrating Lymphocytes
The above data suggested that the gentle method we used for isolating lymphocytes from tissues (see Materials and Methods)4 preserved the predicted homing phenotypes of the isolated cells. We then examined the expression of chemokine receptors by these cells, focusing on CCR4, CCR5, and CXCR3.
The vast majority of CD4+ cells isolated from the
10 different non-lymphoid tissues examined (Figure 2)
expressed CCR5 and CXCR3 (Figure 2, C
-L; middle and right panels). This is in dramatic contrast to tonsil,
where only very small numbers of CD4+ lymphocytes
expressed CCR5 or CXCR3 (Figure 2B
; far right panel). Nearly all of the
CD4+ populations infiltrating non-lymphoid
tissues contained far more CCR5+ and
CXCR3+ cells than did memory
CD4+ cells from the blood (with the exception of
CXCR3 in the skin, where the pattern was similar to that on
CLA+ cells in the blood11
) (Figure 2A
; middle and right panels). The ubiquity of
CCR5+ and CXCR3+ T cells
within so many diverse tissues suggests that CCR5 and CXCR3 are not
involved in determining the tissue-specificity of lymphocyte homing,
and that CCR5 and CXCR3 expression may be a general phenotype of
tissue-infiltrating lymphocytes. CCR5 and CXCR3 may therefore be more
important with respect to positioning or retention of lymphocytes after
tissue entry.21
Indeed, it is possible that these
receptors may actually be induced after tissue entry.
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. CCR4 was not seen on lamina propria CD4+
cells from any of the intestinal segments (including jejunum, ileum and
colon, Figure 2, D–F
), or on liver-infiltrating
CD4+ cells (Figure 2G)
. CCR4 was expressed at
very high levels only in the skin (Figure 2C)
. CCR4 was expressed at
lower levels by synovial fluid CD4+ cells from
autoimmune arthritis patients (rheumatoid, Figure 2K
and psoriatic,
Figure 2L
) but not from osteoarthritis patients (Figure 2J)
. CCR4 was
also expressed at low levels on bronchial CD4+
cells (Figure 2I)
and even more rarely by lung interstitial
CD4+ cells (Figure 2H)
. Like CCR5 and CXCR3,
there was little CCR4 expression in the tonsil (Figure 2B)
. Relative CCR4 Expression Levels on CD4 Cells from Systemic Tissues
The expression of CCR4 by skin-derived lymphocytes appeared
significantly higher than its expression by bronchial or synovial
cells. This higher expression was confirmed by additional experiments
using blood CLA+ lymphocytes from tissue donors
as an internal standard (Figure 3)
. Flow
cytometry of CCR4 on tissue-infiltrating lymphocytes was overlaid
directly on that of
CD4+CLA+ blood lymphocytes
from the same patient (Figure 3, A–D)
. Only skin-derived cells
expressed CCR4 at a level matching that of
CD4+CLA+ cells from
donor-matched blood (Figure 3A)
. The median CCR4 expression by
bronchial or synovial cells was at least an order of magnitude less
that of donor-matched
CD4+CLA+ blood cells
(Figure 3, B–D)
.
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We hypothesized that differences in CCR4 expression levels may be
functionally relevant in lymphocyte trafficking. We therefore sorted
peripheral blood memory CD4+ lymphocytes into
four categories of CCR4 expression (Figure 4A)
: CCR4neg cells
were sorted to match the level of staining of the isotype control
antibody, CCR4lo cells were sorted to have a
level of expression similar to that of synovial fluid or BAL cells
(Figure 2)
, CCR4hi cells were sorted to have a
level of expression similar to that of skin-homing cells (Figure 2)
,
and CCR4int cells were sorted from the region
between the CCR4lo and
CCR4hi cells and contained some overlap with both
populations.
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. Interestingly, the small number
of cells becoming adherent in the CCR4lo sorted
population could be accounted for largely by overlap with the
CCR4int sorted population. All populations
adhered similarly in response to SDF-1 (
90 to 95% of input, not
shown), and TARC responses were normalized to the SDF-1 response for
each population. As seen for adhesion, all four populations responded
similarly to SDF-1 in chemotaxis assays a (68 to 74% of input,
not shown), and the TARC responses were also normalized to the
SDF-1a response for each population. CCR4hi
cells showed the best TARC response (Figure 4C)
. Surprisingly, lower
levels of CCR4 expression corresponded with reduced chemotaxis to TARC
(Figure 4C)
, similar to the pattern seen in the adhesion assay. To rule
out the possibility that the optimal chemotactic concentration of TARC
was different for cells bearing different levels of CCR4, we titered
TARC on sorted CCR4lo and
CCR4hi cells in the chemotaxis assay (Figure 4D)
.
We found that the difference in migratory performance between the two
sorted populations could not be accounted for by a difference in
relative sensitivity to TARC. Similar chemotaxis results were obtained
with MDC, another ligand for CCR4 (data not shown). |
Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionsReferences |
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Tissue-Specific Adhesion Molecules
Our findings strongly support the importance of adhesion molecules
classically associated with tissue-specific lymphocyte
homing.1
As reported previously,
CLA+ lymphocytes, 20% of circulating memory T
cells, were enriched to almost 100% in skin-infiltrating populations,
but virtually absent from the jejunal lamina propria.17
Conversely,
4ß7+
lymphocytes, also 20% of circulating memory
CD4+ cells, were enriched to nearly 100% in
jejunal lamina propria-infiltrating populations, but absent in the
skin. CLA and 4ß7
expressing lymphocytes were rare in memory populations isolated from
lung and tonsil, where these molecules are not thought to play a role
in homing. In contrast to the skin and jejunum, SF contained
CLA+ and
4ß7+
memory CD4+ subpopulations in proportions similar
to the blood. The SF data may reflect a reduction in homing specificity
at sites of intense chronic inflammation. It is noteworthy that
immunophenotypically-defined skin-homing, gut-homing, and other memory
lymphocyte types are found together in synovial fluid from autoimmune
arthritis cases. In contrast, naive lymphocytes are apparently excluded
from this compartment. This finding may imply the existence of a
previously unrecognized homing pathway that distinguishes between
memory and naive cells, but does not distinguish among the various
tissue-specialized memory lymphocyte subsets. This may shed light on a
previous finding that intestine-derived lymphocytes are able to
interact with synovial endothelium.25
Instead of implying
that autoimmune arthritis is mediated by intestine-derived lymphocytes,
the finding may simply demonstrate another manifestation of the notion
that any type of memory cell can potentially enter this compartment.
Expression of CCR5 and CXCR3 by Tissue-Infiltrating Lymphocytes
Our survey of lymphocytes from various human tissues has shown
that the vast majority of resident tissue
CD4+ cells express both CXCR3 and CCR5.
Expression of these inflammatory receptors has been previously reported
for tissue lymphocytes in the intestines,7
liver,10
brain,9
and synovial
fluid,11
and explained as particularly important for
specific homing/localization to each location. The strong expression of
CCR5 and CXCR3 by lymphocytes from the wide variety of tissues shown
here however suggests that these receptors are unlikely to contribute
to the specificity of lymphocyte homing per se. However,
their near ubiquity implies important, albeit not yet understood, roles
in tissue lymphocyte homing and/or function. We and others have found
that only about 25 to 30% of circulating memory
CD4+ lymphocytes co-express CCR5 and CXCR3 (E.J.
Kunkel and J.J. Campbell, unpublished data).11
It is
possible that tissue-infiltrating lymphocytes are recruited only from
this double-positive population. However, the correlation between CD69
expression (an activation marker) and CXCR3/CCR5 expression raises the
possibility that both receptors may be induced after tissue entry. In
either scenario, CCR5 and CXCR3 likely facilitate the movement of
lymphocytes within target tissues.26,27
The CCR5 ligands,
RANTES and MIP-1, are known to be produced by activated dendritic
cells,28
suggesting a potential role for CCR5 in mediating
co-localization of lymphocytes and dendritic cells within tissues.
Alternatively, one or both of these receptors may contribute to
retention of activated cells within tissues. Finally, CCR5 and/or CXCR3
up-regulation on lymphocytes in tissues may enhance the ability of
these lymphocytes, once they return to the circulation, to subsequently
be recruited to active sites of subacute inflammation where CCR5 and
CXCR3 ligands may play a more prominent role.
Expression of CCR4 by Tissue-Infiltrating Lymphocytes
In contrast to CCR5 and CXCR3, lymphocyte expression of CCR4 was only observed on lymphocytes from a subset of non-intestinal tissues, and only at high levels within the skin (as will be discussed further below). The enriched expression of CCR4 by skin-infiltrating lymphocytes supports the model that the combined expression of CLA and CCR4 is necessary for fruitful interaction between cutaneous venules and circulating skin-homing lymphocytes.5 Cutaneous venules are known to express E-selectin, the ligand for CLA,29 and TARC, one of the chemokine ligands for CCR4.5
Our finding that CCR4 is strongly expressed by lymphocytes isolated directly from DTH- or contact hypersensitivity-inflamed skin in vivo would tend to argue against the notion that CCR4 is a marker for Th2 cells, as suggested by in vitro models of polarized T cell development,30-32 because DTH and contact hypersensitivity responses are classical, universally accepted models for Th1-mediated inflammation.
CCR4 Expression Levels and Function
We have previously proposed that high numbers of cell-surface chemokine receptors may be necessary to mediate adhesion triggering under shear, whereas smaller numbers of receptors per cell may be sufficient to mediate chemotaxis.33 By this argument, only skin-infiltrating lymphocytes (those with the highest CCR4 expression) might express sufficiently high levels of CCR4 to mediate rapid adhesion-triggering under shear.5 Lymphocytes expressing lower levels of CCR4 (as in BAL fluid) could, by the same argument, use this receptor for chemotaxis. We were therefore surprised to find that peripheral blood lymphocytes sorted for low levels of CCR4 expression (as determined by two mAbs to CCR4) responded very poorly to CCR4 ligands in both adhesion and chemotaxis assays.
There is, however, recent evidence proposing a role for CCR4 in
inflammation at these sites (ie, bronchi and synovium). Bronchial
epithelial cells stimulated with both tumor necrosis factor- and
interferon-
produce large amounts of TARC,34
and
activated macrophages (found in synovial tissue) are extremely potent
sources of another CCR4 ligand, MDC.35
If the low levels
of CCR4 observed on BAL and synovial fluid lymphocytes are genuine,
this receptor may potentially mediate chemotaxis at these sites. CCR4
on these lymphocytes may serve to chemotactically guide lung
lymphocytes to the epithelial layer once they have entered
peri-bronchial tissues. Similarly, synovial lymphocytes may be guided
through the tissue by using gradients of MDC secreted by resident
activated macrophages. Expression of CCR4 ligands may also play roles
in other aspects of immunity not related to lymphocyte localization.
Synovial lymphocytes from autoimmune arthritis patients have previously been shown to have some characteristics of skin-homing cells.36 This has led to the proposal (especially in the case of psoriatic arthritis) that attraction of cutaneous lymphocytes to the synovium may be a component of the disease mechanism.36 Our findings demonstrate that lymphocytes from synovial fluid do indeed contain cells of the cutaneous homing phenotype, but cells of intestinal and other homing phenotypes are present as well. Thus, cutaneous lymphocytes are not enriched in the synovial fluid above their relative numbers in normal peripheral blood. These findings could be explained by the notion that control of memory T cell homing specificity has broken down in such chronic autoimmune disorders.
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Conclusions |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionsReferences |
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4ß7 within skin and
intestine, respectively, is consistent with a role for these molecules
in tissue specific homing. 4) CCR5 and CXCR3 are nearly ubiquitously
expressed by lymphocytes that have infiltrated non-lymphoid tissues,
and are thus unlikely to contribute to the determination of tissue
specificity. 5) CCR4 is expressed by CD4+ T cells
from only a subset of non-intestinal tissues, and expressed at the
highest, most functional levels only by skin-infiltrating
CD4+ cells.
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Acknowledgements |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionsReferences |
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Footnotes |
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TopAbstractMaterials and MethodsResultsDiscussionConclusionsReferences |
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Supported by NIH grant AI-46784 to J.J.C. and NIH grants GM-37734, AI-47822, GM-56527 and AI-37832 and a Merit Award from the Veterans Administration to E.C.B. E.J.K. is a recipient of an Arthritis Foundation Postdoctoral Fellowship.
Accepted for publication October 9, 2001.
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References |
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4ß7. J Immunol 1998, 161:4227-4235This article has been cited by other articles:
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C. M. Freeman, V. R. Stolberg, B.-C. Chiu, N. W. Lukacs, S. L. Kunkel, and S. W. Chensue CCR4 Participation in Th Type 1 (Mycobacterial) and Th Type 2 (Schistosomal) Anamnestic Pulmonary Granulomatous Responses J. Immunol., September 15, 2006; 177(6): 4149 - 4158. [Abstract] [Full Text] [PDF]
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B. Ma, W. Liu, R. J. Homer, P. J. Lee, A. J. Coyle, J. M. Lora, C. G. Lee, and J. A. Elias Role of CCR5 in the Pathogenesis of IL-13-Induced Inflammation and Remodeling. J. Immunol., April 15, 2006; 176(8): 4968 - 4978. [Abstract] [Full Text] [PDF]
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R. A. Clark, B. Chong, N. Mirchandani, N. K. Brinster, K.-i. Yamanaka, R. K. Dowgiert, and T. S. Kupper The Vast Majority of CLA+ T Cells Are Resident in Normal Skin J. Immunol., April 1, 2006; 176(7): 4431 - 4439. [Abstract] [Full Text] [PDF]
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S.-h. Ho, L. Shek, A. Gettie, J. Blanchard, and C. Cheng-Mayer V3 Loop-Determined Coreceptor Preference Dictates the Dynamics of CD4+-T-Cell Loss in Simian-Human Immunodeficiency Virus-Infected Macaques J. Virol., October 1, 2005; 79(19): 12296 - 12303. [Abstract] [Full Text] [PDF]
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J. Yoo, M. Omori, D. Gyarmati, B. Zhou, T. Aye, A. Brewer, M. R. Comeau, D. J. Campbell, and S. F. Ziegler Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin J. Exp. Med., August 15, 2005; 202(4): 541 - 549. [Abstract] [Full Text] [PDF]
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C. de Lemos, J. E. Christensen, A. Nansen, T. Moos, B. Lu, C. Gerard, J. P. Christensen, and A. R. Thomsen Opposing Effects of CXCR3 and CCR5 Deficiency on CD8+ T Cell-Mediated Inflammation in the Central Nervous System of Virus-Infected Mice J. Immunol., August 1, 2005; 175(3): 1767 - 1775. [Abstract] [Full Text] [PDF]
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S. Ying, B. O'Connor, J. Ratoff, Q. Meng, K. Mallett, D. Cousins, D. Robinson, G. Zhang, J. Zhao, T. H. Lee, et al. Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity J. Immunol., June 15, 2005; 174(12): 8183 - 8190. [Abstract] [Full Text] [PDF]
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V. Monceaux, L. Viollet, F. Petit, R. H. T. Fang, M.-C. Cumont, J. Zaunders, B. Hurtrel, and J. Estaquier CD8+ T Cell Dynamics during Primary Simian Immunodeficiency Virus Infection in Macaques: Relationship of Effector Cell Differentiation with the Extent of Viral Replication J. Immunol., June 1, 2005; 174(11): 6898 - 6908. [Abstract] [Full Text] [PDF]
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E. S. Baekkevold, M.-A. Wurbel, P. Kivisakk, C. M. Wain, C. A. Power, G. Haraldsen, and J. J. Campbell A role for CCR4 in development of mature circulating cutaneous T helper memory cell populations J. Exp. Med., April 4, 2005; 201(7): 1045 - 1051. [Abstract] [Full Text] [PDF]
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A. Burman, O. Haworth, D. L. Hardie, E. N. Amft, C. Siewert, D. G. Jackson, M. Salmon, and C. D. Buckley A Chemokine-Dependent Stromal Induction Mechanism for Aberrant Lymphocyte Accumulation and Compromised Lymphatic Return in Rheumatoid Arthritis J. Immunol., February 1, 2005; 174(3): 1693 - 1700. [Abstract] [Full Text] [PDF]
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L. J. Picker, S. I. Hagen, R. Lum, E. F. Reed-Inderbitzin, L. M. Daly, A. W. Sylwester, J. M. Walker, D. C. Siess, M. Piatak Jr., C. Wang, et al. Insufficient Production and Tissue Delivery of CD4+ Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection J. Exp. Med., November 15, 2004; 200(10): 1299 - 1314. [Abstract] [Full Text] [PDF]
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C.-J. Chang, K.-F. Tai, S. Roffler, and L.-H. Hwang The Immunization Site of Cytokine-Secreting Tumor Cell Vaccines Influences the Trafficking of Tumor-Specific T Lymphocytes and Antitumor Efficacy against Regional Tumors J. Immunol., November 15, 2004; 173(10): 6025 - 6032. [Abstract] [Full Text] [PDF]
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 J. Blanco, J. Barretina, B. Clotet, and J. A. Este R5 HIV gp120-mediated cellular contacts induce the death of single CCR5-expressing CD4 T cells by a gp41-dependent mechanism J. Leukoc. Biol., October 1, 2004; 76(4): 804 - 811. [Abstract] [Full Text] [PDF]
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 C. Pilette, J.N. Francis, S.J. Till, and S.R. Durham CCR4 ligands are up-regulated in the airways of atopic asthmatics after segmental allergen challenge Eur. Respir. J., June 1, 2004; 23(6): 876 - 884. [Abstract] [Full Text] [PDF]
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P. Schaerli, L. Ebert, K. Willimann, A. Blaser, R. S. Roos, P. Loetscher, and B. Moser A Skin-selective Homing Mechanism for Human Immune Surveillance T Cells J. Exp. Med., May 3, 2004; 199(9): 1265 - 1275. [Abstract] [Full Text] [PDF]
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D. Atanackovic, A. Block, A. de Weerth, C. Faltz, D. K. Hossfeld, and S. Hegewisch-Becker Characterization of Effusion-Infiltrating T Cells: Benign versus Malignant Effusions Clin. Cancer Res., April 15, 2004; 10(8): 2600 - 2608. [Abstract] [Full Text] [PDF]
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C. Pilette, S. R. Durham, J.-P. Vaerman, and Y. Sibille Mucosal Immunity in Asthma and Chronic Obstructive Pulmonary Disease: A Role for Immunoglobulin A? Proceedings of the ATS, April 1, 2004; 1(2): 125 - 135. [Abstract] [Full Text] [PDF]
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J. C. Dudda, J. C. Simon, and S. Martin Dendritic Cell Immunization Route Determines CD8+ T Cell Trafficking to Inflamed Skin: Role for Tissue Microenvironment and Dendritic Cells in Establishment of T Cell-Homing Subsets J. Immunol., January 15, 2004; 172(2): 857 - 863. [Abstract] [Full Text] [PDF]
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 K. Greiner, C. C. Murphy, F. Willermain, L. Duncan, J. Plskova, G. Hale, J. D. Isaacs, J. V. Forrester, and A. D. Dick Anti-TNF{alpha} Therapy Modulates the Phenotype of Peripheral Blood CD4+ T Cells in Patients with Posterior Segment Intraocular Inflammation Invest. Ophthalmol. Vis. Sci., January 1, 2004; 45(1): 170 - 176. [Abstract] [Full Text] [PDF]
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 T. S. Kupper Immunologic Targets in Psoriasis N. Engl. J. Med., November 20, 2003; 349(21): 1987 - 1990. [Full Text] [PDF]
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D. M. Conroy, L. A. Jopling, C. M. Lloyd, M. R. Hodge, D. P. Andrew, T. J. Williams, J. E. Pease, and I. Sabroe CCR4 blockade does not inhibit allergic airways inflammation J. Leukoc. Biol., October 1, 2003; 74(4): 558 - 563. [Abstract] [Full Text] [PDF]
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T. Ishida, A. Utsunomiya, S. Iida, H. Inagaki, Y. Takatsuka, S. Kusumoto, G. Takeuchi, S. Shimizu, M. Ito, H. Komatsu, et al. Clinical Significance of CCR4 Expression in Adult T-Cell Leukemia/Lymphoma: Its Close Association with Skin Involvement and Unfavorable Outcome Clin. Cancer Res., September 1, 2003; 9(10): 3625 - 3634. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, A. L. Miller, and C. M. Hogaboam Chemokine Receptors in Asthma: Searching for the Correct Immune Targets J. Immunol., July 1, 2003; 171(1): 11 - 15. [Full Text] [PDF]
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 W. Iijima, H. Ohtani, T. Nakayama, Y. Sugawara, E. Sato, H. Nagura, O. Yoshie, and T. Sasano Infiltrating CD8+ T Cells in Oral Lichen Planus Predominantly Express CCR5 and CXCR3 and Carry Respective Chemokine Ligands RANTES/CCL5 and IP-10/CXCL10 in Their Cytolytic Granules: A Potential Self-Recruiting Mechanism Am. J. Pathol., July 1, 2003; 163(1): 261 - 268. [Abstract] [Full Text] [PDF]
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A. Ito, A. Matejuk, C. Hopke, H. Drought, J. Dwyer, A. Zamora, S. Subramanian, A. A. Vandenbark, and H. Offner Transfer of Severe Experimental Autoimmune Encephalomyelitis by IL-12- and IL-18-Potentiated T Cells Is Estrogen Sensitive J. Immunol., May 1, 2003; 170(9): 4802 - 4809. [Abstract] [Full Text] [PDF]
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P. Gao, X.-Y. Zhou, Y. Yashiro-Ohtani, Y.-F. Yang, N. Sugimoto, S. Ono, T. Nakanishi, S. Obika, T. Imanishi, T. Egawa, et al. The unique target specificity of a nonpeptide chemokine receptor antagonist: selective blockade of two Th1 chemokine receptors CCR5 and CXCR3 J. Leukoc. Biol., February 1, 2003; 73(2): 273 - 280. [Abstract] [Full Text] [PDF]
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T. L. Humphreys, C. T. Schnizlein-Bick, B. P. Katz, L. A. Baldridge, A. F. Hood, R. A. Hromas, and S. M. Spinola Evolution of the Cutaneous Immune Response to Experimental Haemophilus ducreyi Infection and Its Relevance to HIV-1 Acquisition J. Immunol., December 1, 2002; 169(11): 6316 - 6323. [Abstract] [Full Text] [PDF]
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V. Szanya, J. Ermann, C. Taylor, C. Holness, and C. G. Fathman The Subpopulation of CD4+CD25+ Splenocytes That Delays Adoptive Transfer of Diabetes Expresses L-Selectin and High Levels of CCR7 J. Immunol., September 1, 2002; 169(5): 2461 - 2465. [Abstract] [Full Text] [PDF]
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