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Departments of
*
Cell Processing and
Clinical Immunology and AIDS Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; and
Japanese Red Cross Central Blood Center, Tokyo, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, monocyte chemoattractant
protein-1, RANTES, MIP-3, monokine induced by IFN-
, and
IFN--inducible protein-10 was significantly impaired compared with
those of PB T cells. In contrast, the ability of CB T cells to migrate
to MIP-3
, 6Ckine, and stromal cell-derived factor-1 was greater
than that of PB T cells, and these events were correlated with the
expression levels of CCR-7 and CXCR-4, respectively. Engagement of CD3
and CD28 specifically up-regulated CXCR-3 expression and chemotaxis to
monokine induced by IFN- and IFN--inducible protein-10, whereas
this stimulation down-regulated CCR-7 expression and chemotaxis to
MIP-3 and 6Ckine in PB T cells, but not in CB T cells. These results
suggest that PB T cells and CB T cells exhibit distinct chemokine
responsiveness via different chemokine receptor
repertoire. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Accumulating results suggest that the interaction between chemokines and their receptors is crucial to the selective migration of circulating peripheral blood (PB) T cells to sites of inflammatory reactions or secondary lymphoid organs, including lymph nodes and Peyer’s patches (2, 3, 4). A pattern of chemokine responsiveness and chemokine receptor expressions in PB T cells is implicated to be correlated with the properties of their subsets, including memory phenotype vs naive phenotype (3, 4, 5, 6, 7, 8, 9, 10) and Th1s vs Th2s (11, 12, 13, 14). However, the chemokine receptor expressions and responsiveness of cord blood (CB) T cells remain unclear.
In this study, we examined the expression of CCRs and CXCRs in CB T cells and their chemotactic migratory ability in response to their respective ligands.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The medium used throughout was RPMI 1640 supplemented with 2 mM
L-glutamine, 50 µg/ml streptomycin, 50 U/ml penicillin,
and 10% heat-inactivated FCS. IL-8, macrophage-inflammatory protein
(MIP)-1, monocyte chemoattractant protein (MCP)-1, RANTES, eotaxin,
MIP-3, MIP-3, 6Ckine, growth-related oncogene , monokine
induced by IFN- (MIG), IFN--inducible protein-10 (IP-10), and
stromal cell-derived factor (SDF)-1, and B cell-attracting
chemokine-1 were purchased from PeproTech (London, U.K.).
Preparation of mAbs to CCR-1 and CCR-3
The preparation of mAbs to CCR-1 (IgG1
, clone 141-2) and
CCR-3 (IgG1, clone 444-11) was performed as described previously
(15, 16). The specificities of the mAbs and their lack of
cross-reactivity were verified by the staining of CCR-1- and
CCR-3-expressing transfectants (15, 16) Their
specificities were also certified using anti-CCR-1 mAb (R&D
Systems, Minneapolis, MN) and anti-CCR-3 mAb (R&D Systems).
Preparation and culture of T cells and their subsets
Samples of PB and umbilical CB were obtained according to institutional guidelines with informed consent from all healthy volunteers (each 40 individuals). Mononuclear cells (MNCs) from each sample were obtained by Ficoll-Hypaque (Pharmacia Fine Chemicals, Uppsala, Sweden) density centrifugation, and purification of T cells was performed by E-rosetting (17). T cell preparations were typically >97% pure, as indicated by anti-CD3 mAb staining (Becton Dickinson, Mountain View, CA). For preparation of CD45RO+ T cells and CD45RA+ T cells from PB T cells and CB T cells, cells were negatively selected with anti-CD45RA mAb (PharMingen, San Diego, CA) and anti-CD45RO mAb (PharMingen) in combination with anti-mouse IgG mAb-conjugated immunomagnetic beads (Dynal, Oslo, Norway). The purities of these preparations were more than 98% by flow-cytometric analysis with FITC-conjugated anti-CD45RA mAb and PE-conjugated anti-CD45RO mAb (all from Becton Dickinson).
Stimulation of T cells
PB T cells and CB T cells were either unstimulated or stimulated with a combination of immobilized mAbs to CD3 and CD28 (all from PharMingen) for 3 days at 37°C (17), and cells were used for subsequent experiments.
Flow cytometry
For surface marker analysis, cells were treated with 0.5% mouse serum (Dako, Glostrup, Denmark) for 15 min at 4°C to block the FcR, and stained with the following mAbs conjugated to FITC or PE for direct fluorescein: CD3, CD45RA, and CD45RO (Becton Dickinson); CCR-2, CXCR-1, CXCR-2, CXCR-3, and CXCR-5 (R&D Systems); CD28, CCR-5, and CXCR-4 (PharMingen). Cells were also stained with the corresponding FITC- or PE-conjugated isotype-matched control mAb (all from Becton Dickinson). In indirect staining, cells were incubated with biotin-conjugated anti-CCR-1 mAb (clone 141-2) or biotin-conjugated anti-CCR-3 mAb (clone 444-11) for 30 min at 4°C, washed twice with cold PBS, and subsequently stained with FITC-conjugated avidin (Becton Dickinson) for 30 min at 4°C. Thereafter, cells were washed twice, and suspended in PBS containing 0.2 µg/ml propidium iodide (Sigma; St. Louis, MO) to exclude dead cells. Analysis of fluorescence staining was performed with a FACScalibur flow cytometer (Becton Dickinson) and CELLQuest Software. The expression levels of CCR-1 and CCR-3 were also confirmed by flow cytometry with anti-CCR-1 mAb (R&D Systems) and anti-CCR-3 mAb (R&D Systems).
Semiquantitative RT-PCR
RNA from each sample (5 x 106) was
isolated using Trizol LS reagent (Life Technologies, Gaithersburg, MD).
The first strand cDNA kit (SuperScript Preamplication System; Life
Technologies) was used to make cDNA (20 µl) from 5 µg of each RNA.
Amplification of each cDNA (1 µl) was performed with a SuperTaq
Premix kit (Sawady Technology, Tokyo, Japan) using the specific primers
of CCR-7 (16) and CXCR-3 (18). Specific
primers for -actin (Toyobo, Osaka, Japan) were also used for
amplification. To activate DNA polymerase, preheating (95°C for 5
min) was performed. The reaction mixture was then subjected to 30
cycles of PCR under the following conditions: CCR-7, 94°C for 1 min,
61.5°C for 2 min, and 72°C for 3 min; CXCR-3, 94°C for 30 s,
56°C for 30 s, and 72°C for 30 s. Following these
procedures, a final extension (72°C for 10 min) was performed. PCR
products were analyzed by electrophoresis through 2% agarose gels and
visualized under UV light after ethidium bromide staining.
Assay for chemotaxis
The in vitro migration of T cells and their subsets was assessed in a Transwell cell culture chamber (Costar, Cambridge, MA), as described previously (3, 4, 5, 6, 7, 12), with some modifications (15, 16). In brief, 5-µm-pore-size polycarbonate filters were precoated with 5 µg of gelatin (WAKO, Osaka, Japan) in a volume of 50 µl on the lower surface, and dried overnight at room temperature. The coated filters were washed in PBS and then dried immediately before use. Cells (5 x 105/100 µl) were added to the upper compartment of the chamber. Chemokines (1–100 ng/ml) diluted in serum-free culture medium (600 µl) were loaded in the lower compartment. After a 2-h incubation at 37°C, the filters were fixed with methanol and stained with hematoxylin and eosin (all from WAKO). Cells on the upper surface of the filters were removed by wiping with cotton swabs. Cells that had migrated to various areas of the lower surface were manually counted under a microscope at a magnification of x200, and each assay was performed in triplicate. The data are expressed as number of migrated cells/high power field. We also performed checkerboard control assay for each distinct chemotaxis assay, and the migration was not observed in the absence of a chemokine gradient (data not shown), indicating that the migratory response to these chemokines by these T cells was chemotactic and not due to chemokinesis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Accumulating results indicate that leukocyte migration from
the circulation into inflammatory sites is mediated through chemotaxis,
which is regulated by specific interactions between chemokine and their
receptors (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). To better understand the chemokine
receptor expressions and responsiveness of CB T cells, PB T cells and
CB T cells were isolated from PBMNCs and CBMNCs (Fig. 1
A) (17), and the
chemotactic properties of the these T cells were examined.
Flow-cytometric analysis showed that PB T cells expressed CCR-1, CCR-2,
CCR-5, CCR-6, CXCR-3, and CXCR-4, but not CXCR-1, CXCR-2, and CXCR-5,
on their surface (Table I and Fig. 1B), consistent with previous reports (2, 3, 4, 5, 6, 7, 8, 9).
In contrast, CB T cells expressed CXCR-4, but not any CCRs or other
CXCRs, on their surface (Table I and Fig. 1B).
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shows that the transcriptional
expression of CCR-7 was higher in CB T cells than PB T cells (Fig. 5).
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To determine the chemokine responsiveness of PB T cells and CB T
cells, the chemotactic migratory abilities of PB T cells and CB T cells
in response to various CC and CXC chemokines were examined (Table II and Fig. 2). PB T cells exhibited chemotactic
migratory abilities in responses to MIP-1 (for CCR-1 and CCR-5),
MCP-1 (for CCR-2 and CCR-4), RANTES (for CCR-1, CCR-3, and CCR-5),
MIP-3 (for CCR-6), MIP-3 (for CCR-7), 6Ckine (for CCR-7), MIG
(for CXCR-3), IP-10 (for CXCR-3), and SDF-1 (for CXCR-4). CB T cells
exhibited significantly less of a chemotactic migratory response to
inflammatory chemokines, including MIP-1, MCP-1, RANTES, MIP-3,
MIG, and IP-10, than those of PB T cells. In contrast, the ability of
CB T cells to migrate to secondary lymphoid tissue-related chemokines
such as MIP-3 and 6Ckine as well as SDF-1, which is a chemokine
secreted from bone marrow (BM) stromal cells, was higher than that of
PB T cells. We also observed neither cell type migrated in response to
eotaxin (for CCR-3), IL-8 (for CXCR-1 and CXCR-2), growth-related
oncogene (for CXCR-2), or B cell-attracting chemokine-1 (for
CXCR-5).
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To address the feature of chemokine responsiveness of PB T cells
and CB T cells, CD45RO+ and
CD45RA+ T subsets were isolated (Fig. 3A), and the cell surface
expressions of CCRs and CXCRs were examined (Table I
and Fig. 3B). CD45RO+ PB T cells expressed
CCR-1, CCR-2, CCR-5, CCR-6, CXCR-3, and CXCR-4, whereas
CD45RA+ PB T cells expressed only CCR-1 and
CXCR-4. In contrast, CD45RA+ CB T cells expressed
CXCR-4, but no CCRs or other CXCRs, on the cell surface. We also
observed that the level of the transcriptional expression of CCR-7 was
lower in CD45RO+ PB T cells than
CD45RA+ PB T cells and
CD45RA+ CB T cells (Fig. 5).
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We also investigated the chemotactic migratory responses of
CD45RO+ subsets and CD45RA+
subsets of PB T cells and CB T cells to CC and CXC chemokines (Table II
and Fig. 4).
CD45RO+ PB T cells exhibited more potent
chemotactic migratory ability in response to MIP-1, MCP-1, RANTES,
MIP-3, MIG, and IP-10 than those of CD45RA+ PB
T cells. Interestingly, the responsiveness of
CD45RA+ CB T cells to MIP-1 and
RANTES was less than that of CD45RA+ PB
T cells. In contrast, the ability of CD45RO+ PB T
cells to migrate to MIP-3, 6Ckine, and SDF-1 was lower than that
of CD45RA+ subsets of PB T cells and CB T
cells.
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We further examined the effect of mAbs to CD3 and CD28 on the
chemokine receptor expressions and responsiveness in PB T cells and CB
T cells. Treatment with mAbs to CD3 and CD28 caused enhancements of the
expressions of cell surface product and transcript of CXCR-3 and
chemotaxis to MIG and IP-10 in PB T cells as well as
CD45RO+ PB T cells and
CD45RA+ PB T cells, while this stimulation failed
to induce these events in CB T cells as well as
CD45RA+ CB T cells as compared with unstimulated
cells (Tables I and II, Fig. 5). In
contrast, this stimulation reduced transcriptional expression of CCR-7
and chemotaxis to MIP-3 and 6Ckine in PB T cells as well as
CD45RO+ PB T cells and
CD45RA+ PB T cells, with little or no effect on
these events in CB T cells as well as CD45RA+ CB
T cells when compared with unstimulated cells (Tables I and II, Fig. 5). Furthermore, ligation by mAbs to CD3 and CD28 slightly reduced cell
surface expression of CXCR-4 and chemotaxis to SDF-1 in PB T cells
as well as CD45RO+ PB T cells and
CD45RA+ PB T cells, but not in CB T cells as well
as CD45RA+ CB T cells (Tables I and II). We also
observed that stimulation with mAbs to CD3 and CD28 had little or no
effect on expressions of other chemokine receptors as well as
chemotaxis to the respective ligands in these cell types (Tables I and II).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We showed that the ability of CB T cells to migrate to certain
inflammatory chemokines was lower than that of PB T cells, while CB T
cells exhibit more potent migrarory response to secondary lymphoid
tissue- and BM-related chemokines than PB T cells (Table II and Fig. 2). Furthermore, these events were associated with the expression
levels of the respective receptors (Table I; Figs. 1B and
5). These results suggest that the distinct chemotactic behavior
between PB T cells and CB T cells may involve different expression
pattern of chemokine receptors.
The pattern of chemokine responsiveness and chemokine receptor
expressions of T cells is reportedly correlated with the properties of
their subsets (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). Consistent with previous reports
(2, 3, 4, 5, 6, 7, 8, 9, 10), CCR-2, CCR-5, CCR-6, and CXCR-3 were expressed on
CD45RO+ PB T cells, but not on
CD45RA+ PB T cells (Table I and Fig. 3).
Furthermore, their chemokine receptor repertoire were correlated with
their chemotactic migratory responses of these cell types to MCP-1,
MIP-3, MIG, and IP-10 (Table II and Fig. 4). In contrast, the cell
surface expression of CCR-1 was comparable between
CD45RA+ PB T cells and
CD45RO+ PB T cells (Table I and Fig. 3)
(8). We also showed that the chemotactic migratory
response of CD45RA+ PB T cells to MIP-1 and
RANTES, which are ligands for CCR-1 and CCR-5, was significantly
decreased as compared with that of CD45RO+ PB T
cells (Table II, Fig. 4) (4, 8). Indeed, we observed that
MIP-1- and RANTES-induced chemotaxis in PB T cells as well as
CD45RO+PB T cells were mainly mediated by CCR-1,
although these events are partly mediated by CCR-5 (Sato et al.,
manuscript submitted for preparation). Furthermore, MIP-1 and RANTES
exhibit more potent binding affinities to CCR-1 than CCR-5
(19). These results indicate that the expression level of
CCR-1 does not simply correlate with the chemokine responsiveness to
its respective ligands in CD45RA+ PB T cells.
These phenomena imply that an inactivation of the downstream of
CCR-1-mediating signaling events may account for the reduced chemokine
responsiveness of CD45RA+ PB T cells to MIP-1
and RANTES as compared with that of CD45RO+ PB T
cells. Further study will be needed to test this possibility.
We showed that CD45RA+ CB T cells as well as
CD45RA+ PB T cells did not express CCR-2, CCR-5,
and CCR-6 on the cell surface, and failed to migrate to their
respective ligands (Tables I and II, Figs. 3 and 4). In contrast, these
cell types exhibited more potent expressions of CCR-7 and CXCR-4 and
migration to their respective ligands than
CD45RO+ PB T cells (Tables I and II, Figs. 4 and 5). Interestingly, unlike CD45RO+ PB T cells and
CD45RA+ PB T cells, CD45RA+
CB T cells did not exhibit cell surface expression of CCR-1 and
chemotaxis for MIP-1 and RANTES (Tables I and II, Figs. 3 and 4).
These results suggest that, although CD45RA+ PB T
cells and CD45RA+ CB T cells exhibit the naive
phenotype, they may exhibit distinct properties in terms of chemotactic
properties.
There are conflicting reports about the role of CD3- and CD28-mediated
signaling events in chemokine receptor expressions and responsiveness
of mature T cells (3, 6, 7, 8, 20). In accordance with some
of the results in the previous reports (6, 7, 8), ligation by
CD3 and CD28 reciprocally regulated receptor expressions of CCR-7 and
CXCR-3 and chemotaxis to their respective ligands in PB T cells as well
as CD45RO+ PB T cells and
CD45RA+ PB T cells (Tables I and II and Fig. 5).
These phenomena imply that antigenic stimulation may allow PB naive T
cells and central memory T cells in secondary lymphoid tissues to
traffick from these sites to peripheral inflammatory sites, while this
stimulation may enhance the migration of PB effector memory T cells
from circulation and other sites to inflammatory regions. In contrast,
the discrepancies in the effect of mAbs to CD3 and CD28 on chemotactic
properties of mature T cells in several groups including ours may be
due to the cell culture condition and experimental design.
The molecular mechanism underlying the inability of mAbs to CD3 and CD28 to regulate the chemokine receptor expressions and responsiveness of CB T cells remains unclear. We (17) and others (21) have reported that protein tyrosine kinase-dependent cascades are activated in CD45RA+ PB T cells as well as CD45RO+ PB T cells following stimulation with mAb to CD3 and CD28, while this stimulation failed to activate these signaling events in CD45RA+ CB T cells. Although the molecular mechanism responsible for the regulation of the chemotactic properties of T cells is still unknown, CD3- and CD28-mediated signaling events involving protein tyrosine kinase-dependent cascades may be involved in this regulation. Thus, our results suggest that the inactivation of these signaling events be responsible for CD3- and CD28-mediated unfunctional regulation of chemokine receptor expressions and responsiveness in CD45RA+ CB T cells.
There appears to be a reduced incidence and severity of acute or extensive chronic graft-vs-host disease (GVHD) in CB transplantation (CBT) when compared with results obtained using PB and BM (22, 23, 24). Accumulating results suggest that reduced incidence and severity of GVHD in CBT may involve an inactivation of donor-derived CB T cells with respect to the secretion of proinflammatory cytokines as well as killing activity due to the expressions of perforin and Fas ligand (17, 25, 26, 27, 28). Clinical manifestations suggested that transplanted T cells derived from BM and PB inoculum may be activated, while transplanted CB T cells may exhibit inactivated status following stimulation with allogeneic Ag and various cytokines (17, 22, 23, 24, 29). Recently, chemotaxis of donor-derived T cells was also implicated as crucial in the initiation and persistence of GVHD in certain animal models (30). It has been shown that certain chemokine receptor expressions and responsiveness were up-regulated in PB T cells by stimulation with several cytokines such as IL-2 and IL-12 (3, 13) as well as mAbs to TCR/CD3 complex and costimulatory molecules (6, 7, 8). In contrast, CB T cells exhibit lower expressions of certain cytokine receptors, including IL-2R and IL-12R, than PB T cells (17, 29). Furthermore, stimulation with allogeneic Ag causes less activation in CB T cells than PB T cells (17). These phenomena imply that allogeneic Ag- and cytokine-stimulated PB T cells and BM T cells may more vigorously infiltrate into peripheral tissues mediated through up-regulation of CXCR-3, whereas these cell types fail to home into secondary lymphoid tissues via down-regulation of CCR-7, following with BM transplantation and PB stem cell transplantation. Conversely, CB T cells may preferentially home into secondary lymphoid tissues via CCR7 after CBT, while these cells failed to home into peripheral inflammatory regions in response to inflammatory chemokines via their respective receptors. These phenomena imply that the inability of CB T cells to migrate to certain inflammatory chemokines may partially account for lower incidence and severity of acute or extensive chronic GVHD of CBT when compared with BM transplantation as well as PB stem cell transplantation.
In summary, our results suggest CB T cells exhibited inability to migrate to certain inflammatory chemokines, while this cell type preferentially migrates to secondary lymphoid tissue- and BM-related chemokines via selective expressions of their respective receptors. A recent series of experiments revealed that the pattern of expression of chemokine receptors in T cell subsets is modulated by various proinflammatory cytokines, and flexible programs of chemokine receptor expression control the tissue-specific migration of effector T cells (3, 12) Although the change of the chemokine receptor expressions and responsiveness of CB T cells following various extracellular stimulation remains unclear, defining this property of CB T cells may clarify the immunological feature of CB.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CXCR, CXC chemokine receptor; BM, bone marrow; CB, cord blood; CBT, CB transplantation; GVHD, graft-vs-host disease; IP-10, IFN--inducible protein-10; MCP, monocyte chemoattractant protein; MIG, monokine induced by IFN-; MIP, macrophage-inflammatory protein; MNC, mononuclear cell; PB, peripheral blood; SDF, stromal cell-derived factor.
Received for publication August 15, 2000. Accepted for publication November 10, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1) and MIP-1 chemokines attract distinct population of lymphocytes. J. Exp. Med. 177:1821. and MIP-1. Science 260:355.. J. Immunol. 162:186.1 reciprocally controls chemotaxis of human peripheral blood monocyte-derived dendritic cells via chemokine receptors. J. Immunol. 164:2285., MIP-1, and RANTES. J. Leukocyte Biol. 60:147.[Abstract]
receptor chain on cord blood mononuclear cells. Blood 87:3344.This article has been cited by other articles:
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