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Departments of
* Pediatrics and
Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University; and
Department of Molecular Preventive Medicine, School of Medicine, University of Tokyo, Japan
Correspondence: Dr. Yuichi Adachi, Department of Pediatrics, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, Toyama 930-0194, Japan. E-mail: yadachi{at}ms.toyama-mpu.ac.jp
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(IFN-)-producing
cells resided exclusively in CXCR3-expressing memory CD4+ T
cells, although IFN- production was found in both memory
CD4+ T cells with and without CCR5 expression. We observed
that CCR4-expressing memory CD4+ T cells in the blood were
more increased in AD patients as compared with normal patients, whereas
CXCR3-expressing memory CD4+ T cells were present in a
lower frequency in AD than seen in normal patients. These results
suggest that CXCR3 and CCR4, but not CCR5 or CCR3, appear to serve as
the useful markers for identification of circulating Th1 and Th2
effector populations.
Key Words: CCR3 • CCR4 • CCR5 • CXCR3 • atopic dermatitis
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(IFN-) and predominantly promote cell-mediated immune responses,
whereas Th2 cells, which produce interleukin-4 (IL-4), IL-5, and IL-13,
are largely involved in humoral immunity including allergic reaction.
The in vivo polarization of the T cell subsets most likely
occurs in the antigen-exposed secondary lymphoid organs. Once naive
CD4+ T cells are primed by antigenic stimuli as memory
cells or effector precursor cells, they migrate from the secondary
lymphoid organs to target tissues through the peripheral blood flow.
Chemokines are a superfamily of small proteins that play a key role in
the leukocyte recruitment process [3
]. Based on a
cysteine motif, CXC, CC, C, and CX3C families have been classified.
Chemokines interact with respective G-protein-coupled receptors
possessing a 7-transmembrane domain. A total of 9 CC (CCR1-9), 5 CXC
(CXCR1-5), 1 C (XCR1), and 1 CX3C (CX3CR1) receptors have been
identified. Recent findings in the in vitro polarized Th
subsets as well as T cell clones have indicated that chemokine
receptors are differentially expressed on Th1 and Th2 effector cells,
resulting in the distribution of these cells into the specified tissue
environments [4
, 5
]. It has been shown that
Th1 cells predominantly express CXCR3 (receptor for IP-10 and Mig) and
CCR5 (receptor for macrophage-inflammatory protein-1
[MIP-1],
MIP-1ß, and RANTES [regulated on activation, normal T expressed and
secreted]) [6
, 7
]. On the other hand, Th2
cells have been found to express CCR3 (receptor for eotaxin, RANTES,
monocyte chemoattractant protein-3 [MCP-3], and MCP-4)
[8
], CCR4 (receptor for TARC and MDC) [7
,
9
, 10
], and CCR8 (receptor for I-309)
[11
, 12
].
It is widely accepted that the balance between Th1 and Th2 cells must determine the outcome of physiological and pathological immune responses, including autoimmune, allergic, and infectious diseases [13 , 14 ]. Atopic dermatitis (AD), which is associated with increased serum IgE levels and eosinophilia, is one example of the Th2-dominated situations [15 ] and is increasing in prevalence in the developed countries [16 ]. In this study, we have analyzed by flow cytometry the expression of some chemokine receptors (CCR3, CCR4, CCR5, or CXCR3) by a defined population of peripheral blood CD4+ T cells, which is possibly circulating as the actual effectors of Th1 or Th2 cells, in AD patients and nonatopic normal individuals. We will show that CXCR3 and CCR4, but not CCR5 or CCR3, are clinically useful in evaluation of circulating Th1- and Th2-type effector cells, respectively, in various immune-mediated disease conditions.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Antibodies and reagents
A generation of a monoclonal antibody (mAb) against CCR4
(KM2160, mouse IgG1) has been described previously [10
].
The purified anti-CXCR3 (1C6, mouse IgG1) and anti-CCR3 (7B11, mouse
IgG2a) mAbs were generously provided by LeukoSite (Cambridge, MA).
Phycoerythrin (PE)-conjugated anti-CCR5 (3A9) and PE-conjugated
anti-IL-5 (TRFK5) mAbs were purchased from PharMingen (San Diego, CA).
PE-conjugated anti-IL-13 (JES10-5A2) mAb was purchased from Beckton
Dickinson (Franklin Lakes, NJ). The following mAbs were obtained from
Becton Coulter (Fullerton, CA): FITC-conjugated anti-CD16 (3G8),
FITC-conjugated anti-CD45RA (2H4), FITC-conjugated anti-IFN-
(45.15), PE-conjugated anti-IL-2 (N7.48A), and PE-conjugated anti-IL-4
(4D9). FITC-conjugated anti-CD3 (UCHT1), FITC-conjugated anti-CD45RO
(UCHL-1), PE-(cyanin 5.1) Cy5-conjugated anti-CD4 (MT310),
FITC-conjugated anti-CD8 (DK25), and FITC-conjugated anti-CD20 (B-Ly1)
mAbs were purchased from Dako Japan (Kyoto, Japan). PE-conjugated
anti-mouse IgG1 and PE-conjugated anti-mouse IgG2a Abs were obtained
from Southern Biotechnology (Birmingham, AL). The culture medium
consisted of RPMI 1640 (Nipro K.K., Tokyo, Japan) supplemented with 2
mM L-glutamine, 10% fetal bovine serum (FBS; Equitech-Bio, Ingram,
TX), 2 x 10-5 M 2-mercaptoethanol, 100 U/ml
penicillin, 100 µg/ml streptomycin, 0.25 µg/ml amphotericin B, and
10 µg/ml gentamycin (GIBCOBRL, Grand Island, NY). Phorbol
12-myristate 13-acetate (PMA), ionomycin, brefeldin A, saponin, and
2-amino-ethylisothiouronium bromide (AET) were purchased from Sigma
(St. Louis, MO). Paraformaldehyde was from Wako (Osaka, Japan).
Cell preparation and immunofluorescence analysis
Peripheral blood mononuclear cells (PBMC) were isolated from
heparinized venous blood by centrifugation on a Ficoll-Hypaque gradient
(Histopaque-1077, Sigma). For staining of chemokine receptors, PBMC
were reacted with anti-CXCR3 (mouse IgG1), anti-CCR4 (mouse IgG1), or
anti-CCR3 (mouse IgG2a) mAbs for 20 min on ice. After washing in
phosphate-buffered saline (PBS, pH 7.3) with 1% FCS and 0.1% sodium
azide (washing buffer), the cells were stained with PE-conjugated
anti-mouse IgG1 or IgG2a Abs for 20 min on ice. After washing in a
washing buffer, the cells were blocked with 5% normal mouse serum for
20 min on ice and then incubated with FITC-conjugated anti-CD45RO mAb
and PE-Cy5-conjugated anti-CD4 mAb for 20 min on ice. For CCR5
expression, PBMC were simultaneously stained with PE-conjugated
anti-CCR5 mAb, FITC-conjugated anti-CD45RO mAb, and PE-Cy5-conjugated
anti-CD4 mAb for 20 min on ice. In some experiments, the cells stained
for CCR3 or CCR4 as above were just reacted with FITC-conjugated
anti-CD3 mAb. The stained samples were analyzed by a flow cytometer
(EPICS XL-MCL; Beckman Coulter KK, Tokyo, Japan).
Isolation and characterization of chemokine receptor-positive and
-negative cells
Memory (CD45RO+) CD4+ T cells with or
without expression of chemokine receptors such as CXCR3, CCR5, and CCR4
were isolated by an electronic sorting using an EPICS ELITE flow
cytometer (Beckman Coulter KK) as described [18
].
E-rosetting T cells was prepared from PBMC by the E-rosette method with
AET-treated sheep red blood cells, followed by centrifugation on a
Ficoll-Hypaque gradient. Next, memory CD4+ T cells were
enriched from E-rosetting T cells by flow cytometric depletion of other
cells stainable with FITC-conjugated anti-CD45RA, anti-CD8, anti-CD16,
and anti-CD20 mAbs. Isolated memory CD4+ T cells were
stained for CCR4, CXCR3, or CCR5 in a PE labeling manner as described
above and further separated into the positive and negative populations
with respect to respective chemokine receptor expression by sorting.
Each step of flow cytometric sorting was performed at two cycles in an
effort to obtain the more purified cell populations, resulting in the
>98% purity as determined by a flow cytometric analysis. The purified
CD4+ T cell populations were stimulated with 20 ng/ml of
PMA and 1 µg/ml of ionomycin in the presence of 10 µg/ml of
brefeldin A for 6 h at 37°C in 5% CO2 and 95% air
and determined for cytokine production. Intracellular synthesis of
cytokines were evaluated at the single-cell level by a flow cytometric
analysis with a modification of the method by Picker et al.
[19
]. Briefly, the stimulated cells were fixed with 4%
paraformaldehyde in PBS at room temperature for 15 min, washed twice in
PBS, and permeabilized with 0.5% saponin in PBS with 1% FBS and 0.1%
sodium azide for 15 min at room temperature. These fixed permeabilized
cells were incubated with a combination of FITC-conjugated anti-IFN-
mAb with PE-conjugated anti-IL-2, anti-IL-4, anti-IL-5, or anti-IL-13
mAbs for 20 min on ice. The cells were analyzed on a flow cytometer
(EPICS XL-MCL).
Statistic analysis
The unpaired Student’s t-test was used to analysis
data. P values <0.05 were considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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) or Th-2 type (IL-4, IL-5, and IL-13) cytokines on
stimulation with PMA and ionomycin was inducible in memory
(CD45RO+) CD4+ T cells freshly isolated from
the blood of AD patients and nonatopic normal donors (data not shown).
Based on the observations above that CXCR3, CCR5, or CCR4, but not
CCR3, were expressed on a fraction of memory CD4+ T cells
in the blood, we further asked whether some of circulating memory
CD4+ T cells expressing these chemokine receptors might
have the ability to produce selectively Th1- or Th2-type cytokines. For
this purpose, memory CD4+ T cells with and without
expression of the corresponding chemokine receptors were purified by
sorting from AD patients or nonatopic normal individuals, stimulated
with PMA and ionomycin, and analyzed for intracellular cytokine
synthesis at a single-cell level by flow cytometry. As shown in
Figure 3
, it was demonstrated that the cells capable of producing IFN-
as Th1-type cytokine were abundant in CXCR3-expressing CD4+
T cells, whereas production of Th2-type cytokines, such as IL-4, IL-5,
and IL-13, was principally seen in those that were CXCR3-negative.
Unexpectedly, IFN- production was almost equally found in both
CCR5-positive and -negative memory CD4+ T cells (Fig. 4
). Concerning CCR4 expression, it should be noted that the cells
capable of producing Th2 cytokines resided exclusively in
CCR4-expressing memory CD4+ T cells, whereas CCR4-negative
ones contained the major population of IFN- producing cells
(Fig. 5
). These results suggested that CXCR3 and CCR4 might be selectively
expressed on Th1- and Th2-type effectors in vivo,
respectively, both of which were actually circulating in the blood
pool. CCR5 did not appear to be useful for identification of Th1-type
effectors in the blood.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Naive T cells are primed with antigenic stimuli and educated under the influence of specified soluble factors and through cognate interactions with dendritic cells, resulting in the development of memory/effector cells, which travel through the circulating pool to migrate to lymphoid tissues or sites of pathologic tissue changes. In light of the current concept that the physiological and pathologic immune status must be determined by the balance of Th1 and Th2 cells, this study was intended to examine wheter the effector cells with Th1 and Th2 cell properties, which express some chemokine receptors, might be actually circulating in the peripheral blood. We used mAbs against CXCR3, CCR5, CCR3, and CCR4 to examine the expression of these chemokine receptors on some circulating memory (CD45RO+) CD4+ T cells in patients with AD as the Th2-dominated disorder and nonatopic normal individuals. Flow cytometric analysis disclosed that mAbs against CXCR3, CCR5, and CCR4 were able to detect a substantial proportion of memory CD4+ T cells in the blood. Consistent with our results, other investigators have observed using the corresponding mAbs that these chemokine receptors are expressed on a fraction of blood CD4+ T cells, which exhibited the CD45RO+ memory phenotype. Qin et al. [21 ] have shown that CCR5-expressing blood CD4+ T cells are CXCR3-positive, but their frequency is lower than those that are CXCR3-positive. We also found that CCR5-expressing CD4+ T cells constituted a part of CXCR3+ memory CD4+ T cells (unpublished observations). Concerning CCR3, Sallusto et al. [8 ] has demonstrated using anti-CCR3 mAb that a small population of memory CD4+ T cells in the blood express CCR3, but our staining trial, despite the use of the same anti-CCR3 mAb, detected only a few CCR3-expressing blood CD4+ T cells. Importantly, studies have shown that Th2 cell clones as well as polarized Th2 cells preferentially express CCR4 and, to the lesser extent, CCR3 [9 , 22 ]. In addition, CCR3 expression on Th2 cell lines is down-regulated by certain cytokines [8 ]. Taken together, it seemed that CCR3, unlike CCR4, might hardly be expressed on circulating Th2-type effector cells.
Regarding the relation between expression of chemokine receptors on
blood CD4+ T cells and cytokine production, previous
studies have expanded in advance respective chemokine
receptor-expressing CD4+ T cells isolated from the blood
and then evaluated the kind of cytokine production by obtained cell
lines [8
, 10
]. Although these experiments
have elegantly verified the correlation between expression of CCR3 or
CCR4 on CD4+ T cells and Th2-type cytokines, their results
do not seem to truly reflect the in vivo situation. The
possibility that blood CD4+ T cells expressing chemokine
receptors might contain the cells that were ready to produce Th1 or Th2
cytokines was investigated in this study. We purified blood memory
CD4+ T cells with or without expression of CXCR3, CCR5, or
CCR4 by sorting and evaluated for their production ability of Th1-type
(IFN-) or Th2-type (IL-4, IL-5, and IL-13) cytokines after brief
stimulation with PMA and ionomycin. Supporting the proposal of the
in vitro studies [6
, 7
,
9
, 10
], we clearly demonstrated that the
cells capable of producing Th1- or Th2-cytokines were exclusively seen
within blood memory CD4+ T cells expressing CXCR3 or CCR4,
respectively. For CCR5, it was found that Th1-type cytokine-producing
cells resided not only in CCR5-positive CD4+ T cells but
also in those that were CCR5-negative. In this regard, Loetscher et al.
[6
] described that CCR5 expressed by Th1 cell clones is
rapidly lost in the absence of IL-2 and stimulation by a combination of
anti-CD3 and anti-CD28 antibodies. Thus, it is likely that some of
Th1-type effector cells are inclined to loss of CCR5 expression in the
blood, which is considered the IL-2-deficient condition.
Based on the evidence above that circulating Th1 or Th2 effector cells appeared to be present within memory CD4+ T cells expressing CXCR3 or CCR4, respectively, the clinical usefulness of expression of CXCR3 and CCR4 was assessed in AD patients as the Th2-dominated disorder. We demonstrated that AD patients showed more increased percentages of CCR4-expressing memory CD4+ T cells than nonatopic normal donors, whereas they had a reduction in CXCR3-expressing CD4+ T cells. Intriguingly, a recent report has shown that most of CCR4-expressing memory CD4+ T cells in the blood have been reported to represent a skin-homing characteristic defined by expression of the cutaneous lymphocyte antigen (CLA) [23 ]. Memory CD4+ T cells expressing both CCR4 and CLA respond well to TARC and MDC, the ligands for CCR4. We found that the majority of CCR4-expressing memory CD4+ T cells in AD patients were CLA-positive (not published data). Because intense TARC expression is seen in the skin of AD, an increase of memory CD4+ T cells coexpressing CCR4 and CLA in the blood seems to be implicated in the pathogenesis of AD. Alternatively, in multiple sclerosis as the Th1-dominated disorder, CXCR3 expressing T cells have been found to increase in the blood and infiltrate into the brain lesions [24 ].
In conclusion, our data show that CXCR3 and CCR4, but not CCR5 or CCR3, serve as the useful markers of Th1 and Th2 effector cells, respectively, in the peripheral blood. Although the number of cases with AD examined here is limited, the clinical significance of expression of these chemokine receptors awaits additional studies on many cases with mild-to-severe AD as well as other immune-mediated diseases.
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ACKNOWLEDGEMENTS |
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Received January 18, 2000; revised April 22, 2000; accepted April 26, 2000.
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REFERENCES |
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 K. KURASHIMA, M. FUJIMURA, S. MYOU, K. KASAHARA, H. TACHIBANA, N. AMEMIYA, Y. ISHIURA, N. ONAI, K. MATSUSHIMA, and S. NAKAO Effects of Oral Steroids on Blood CXCR3+ and CCR4+ T Cells in Patients with Bronchial Asthma Am. J. Respir. Crit. Care Med., September 1, 2001; 164(5): 754 - 758. [Abstract] |
