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CUTTING EDGE |
Department of Internal Medicine and Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75235
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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was also
found to up-regulate expression of early activation markers (CD69,
CD25, and CD154) by anti-CD3-activated CD4+ T cells. In
addition, SDF-1 costimulated proliferation of CD4+ T
cells and production of IL-2, IFN-
, IL-4, and IL-10. Stimulation
with SDF-1 alone did not induce activation marker expression,
proliferation, or cytokine production by the CD4+ T cells.
SDF-1-mediated costimulation was blocked by anti-CXC chemokine
receptor-4 mAb. RANTES also increased activation marker expression by
anti-CD3-stimulated peripheral CD4+ T cells, but less
effectively than SDF-1 did, and did not up-regulate IL-2 production
and proliferation. These results indicate that SDF-1 and CXC chemokine
receptor-4 interactions not only play a role in T cell migration but
also provide potent costimulatory signals to Ag-stimulated T
cells. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and SDF-1ß (1). SDF-1 is
expressed constitutively by various cells and tissues (1, 3) and has chemoattractive activity for monocytes, bone marrow
neutrophils, and early-stage B cell precursors (4, 5). In
addition, SDF-1 is a highly efficient and potent chemoattractant for T
cells (5). Furthermore, SDF-1 induces adhesion of T cells
to ICAM-1 (CD54) (6) by up-regulating the binding activity
of LFA-1 (CD11a/CD18). As a result of these activities, SDF-1 is
thought to play an important role in the attraction of T cells into
specific sites. Mice lacking SDF-1 or CXC chemokine receptor-4 (CXCR4), the unique ligand of SDF-1, exhibited cardiovascular, vascular, and neurologic defects as well as defective B cell lymphopoiesis and a severe impairment of bone marrow myelopoiesis (7, 8, 9). SDF-1 is thought to attract progenitor B cells into the microenvironment of stromal cells where growth and differentiation factors are released (4, 7, 10, 11). These results suggest that in certain circumstances SDF-1 and CXCR4 interactions may have other functions than merely their chemoattractant activities.
To examine other specific activities of SDF-1/CXCR4 interactions, we
examined the capacity of SDF-1 to stimulate T cell activation.
Costimulation with SDF-1 up-regulated the expression of activation
markers, proliferation, and cytokine production by
anti-CD3-activated CD4+ T cells. These
findings indicate that besides a role in chemoattraction, SDF-1 may
play an important role in costimulating activation of Ag-reactive T
cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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PBMCs were isolated by Ficoll-Hypaque (Pharmacia Biotech, Piscataway, NJ) gradient centrifugation from healthy donors. CD4+ T cells were isolated by negative selection using StemSep columns (Stem Cell Technologies, Vancouver, Canada). Purity of the separated CD4+ T cells was more than 95%.
Culture
The purified peripheral CD4+ cells (2
x 106 cells/ml) were cultured in RPMI 1640 with
10% FCS for 6 h because this induced spontaneous expression of
CXCR4, the ligand for SDF-1 on the T cells. For blocking CXCR4, 50
µg/ml anti-CXCR4 mAb (12G5; R&D Systems, Minneapolis, MN) or
isotype-matched control mAb (20102.1; R&D Systems) was added for the
last hour. Afterward, the cells were incubated in medium supplemented
where indicated with SDF-1 or RANTES (R&D Systems) for 2 h.
Subsequently, the CD4+ T cells were transferred
to 96-well microtiter plates with or without anti-CD3 mAb OKT3 (500
ng/microwell (American Type Culture Collection, Manassas, VA)). After
incubation at 37°C for 8 h, surface activation marker expression
was analyzed, cytokine production was analyzed after 8–12 h, and
proliferation was determined after 20–60 h.
FACS analysis
PE-conjugated anti-CXCR4 mAb (12G5; R&D Systems), FITC- or PE-conjugated anti-CD69 mAb (L78; Becton Dickinson, San Jose, CA), FITC-conjugated anti-CD25 mAb (ACT-1; Dako, Carpinteria, CA), and FITC- or PE-conjugated anti-CD154 mAb (TRAP1, PharMingen, San Diego, CA; and 89h76, Becton Dickinson; respectively) were used. The stimulated peripheral CD4+ T cells were stained with the above mAbs and were analyzed with a FACScan (Becton Dickinson).
Proliferation assay
To analyze CD4+ T cell proliferation, the MTT assay (Cell Proliferation Kit I (MTT); Roche, Indianapolis, IN) was used according to the manufacturer’s protocol, and the data reported as OD units.
ELISA
Cytokine concentrations in the culture supernatant were assayed
with ELISA kits for IL-2 (R&D Systems), IFN- (R&D Systems), IL-4
(R&D Systems), and IL-10 (BioSource International, Camarillo, CA).
Cells were cultured for 8 h to assess IL-2 and IFN- production
and for 12 h to determine IL-4 and IL-10 production.
Statistics
To compare proliferation and cytokine expression, the Student t test was used.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Purified peripheral CD4+ T cells expressed
low levels of CXCR4 (Fig. 1
). Culture
with medium for 6 h up-regulated surface CXCR4 expression.
Stimulation with anti-CD3 mAb for 8 h did not further
up-regulate CXCR4 expression beyond that induced by culture in medium
alone.
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Anti-CD3 induced expression of CD69, CD25, and CD154, whereas
SDF-1 did not (Fig. 2). The
combination of anti-CD3 + SDF-1 increased expression of all
activation markers beyond that induced by anti-CD3 alone.
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alone did not
(Fig. 3). However, SDF-1 significantly
enhanced proliferation of anti-CD3-stimulated
CD4+ T cells in a concentration-dependent manner.
Finally, SDF-1 costimulated cytokine production by
anti-CD3-stimulated CD4+ T cells (Fig. 4). Although SDF-1 alone failed to
induce cytokine production by CD4+ T cells, it
caused significant concentration-dependent increases in production of
all cytokines measured by anti-CD3-stimulated
CD4+ T cells.
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-mediated enhancement of CD154, CD69, and CD25 expression
by anti-CD3-stimulated peripheral CD4+ T
cells was blocked by anti-CXCR4 mAb (Fig. 5A and data not shown). In
addition, the enhancement of IL-2 production was blocked by
anti-CXCR4 mAb (Fig. 5B).
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A and data not shown).
However, the degree of the enhancement by RANTES was smaller than that
by SDF-1. Moreover, costimulation with RANTES did not up-regulate
IL-2 production and proliferation by anti-CD3-stimulated peripheral
CD4+ T cells (Fig. 6B and data not
shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is a costimulator of
peripheral CD4+ T cell activation. SDF-1
up-regulated cell surface activation marker expression, proliferation,
and cytokine productions by anti-CD3-stimulated
CD4+ T cells. Stimulation with SDF-1 alone did
not up-regulate any of these functions. It is important to note that
resting peripheral CD4+ T cells express CXCR4,
the ligand for SDF-1 (36–53% positive; n = 3), and
can respond to SDF-1 by migration (data not shown). However,
SDF-1 enhanced activation of CD4+ T cells only
when they were also stimulated with anti-CD3. These results suggest
that SDF-1 may play an important role not only in T cell migration but
also in the effective activation of Ag-stimulated T cells. Recently, it was shown that SDF-1 also binds a non-CXCR4 receptor (12) and could associate with heparan sulfate (13), suggesting that CXCR4 may not be a unique ligand for SDF-1. However, the current data showed that anti-CXCR4 mAb blocked the costimulation of anti-CD3-activated CD4+ T cells by SDF-1, establishing that CXCR4 is necessary for the costimulation by SDF-1.
In the periphery, mainly naive CD4+ T cells express CXCR4 (14, 15, 16), although a substantial percentage (28–37%; n = 3) of memory T cells also express CXCR4. SDF-1 and CXCR4 interactions have been thought to be primarily involved in normal homeostasis by playing a role in the homing of naive T cells to secondary lymphoid organs (17). The current data suggest that SDF-1 and CXCR4 interaction could also play a role in costimulating Ag-activated CD4+ T cells during immune responses in secondary lymphoid organs. Cytokine productions by the CD4+ T cells along with CD154 (CD40 ligand) expression were up-regulated by SDF-1 costimulation. The expressed cytokines and CD40 ligand could activate B cells and DCs in lymphoid organs. Thus, SDF-1 may not only attract T cells to secondary lymphoid organs but also may play an important role in costimulating their ability to effect a successful immune response.
Recently, we found that SDF-1 and CXCR4 interaction might be important for accumulation of CD4+ T cells in rheumatoid arthritis synovium.5 The current data showed that SDF-1 could also be a costimulator of CD4+ T cell activation. Thus, SDF-1 and CXCR4 interactions might act not only to stimulate accumulation of CD4+ T cells in the rheumatoid arthritis synovium but also to costimulate their activation and thereby the capacity to influence the ongoing inflammation in the tissue.
The mechanism by which SDF-1 costimulates anti-CD3- induced T
cell activation is not known. Previous data suggested that SDF-1
inhibited anti-CD3-stimulated phosphorylation of
the TCR signaling molecules ZAP-70, SLP-76, and pp36 in Jurkat cells,
suggesting that SDF-1 could down-regulate T cell activation
(18). However, the current data showed that SDF-1
stimulation up-regulated anti-CD3-mediated activation of peripheral
CD4+ T cells. The explanation for this
discrepancy is currently unknown but could relate to different
signaling capabilities of Jurkat cells and peripheral
CD4+ T cells. Previous data have also indicated
that SDF-1 stimulation induces phosphorylation of Pyk2
via a G-coupled protein pathway (19, 20). Activated Pyk2
is known to activate mitogen-activated protein (MAP) kinases, including
p44/42 MAP (extra-cellular signal-related kinases 1 and 2)
(19, 20, 21), c-Jun amino-terminal kinase, and p38 MAP kinase
(22, 23). In addition, SDF-1 stimulation increased NF-
B
activity (21). These signal pathways may be important in
the capacity of SDF-1 to costimulate anti-CD3-induced T cell
activation. It is noteworthy that SDF-1 alone did not activate
peripheral CD4+ T cells, suggesting that
signaling induced via Pyk2 activation may be insufficient to activate
CD4+ T cells without costimulation by engagement
of the CD3-TCR complex. In this regard, phosphorylation
of Pyk2 has been shown to be induced by engagement of another
costimulatory molecule, 4ß1 (very late Ag 4) (24),
which also is unable to stimulate T cell activation without engagement
of the CD3-TCR complex. Therefore, Pyk2 might be an important molecule
for costimulation by both SDF-1 and very late Ag 4, although it is
likely that different proximal signaling pathways are involved. One of
these could involve phosphoinositide 3-kinase, which has been shown to
be involved in SDF-1 signaling by a number of cell types (25, 26).
It was previously shown that RANTES, macrophage inflammatory protein
(MIP)-1, MIP-1ß, and monocyte chemotactic protein-1 could enhance
CD25 expression, IL-2 production, and proliferation of
anti-CD3-stimulated peripheral CD3+ T cells
(27), and high concentrations of RANTES stimulated T cells
without anti-CD3 stimulation (28). The current data
confirmed that RANTES enhanced early activation marker expression by
anti-CD3-stimulated CD4+ T cells. However,
the effect of RANTES appeared to be considerably weaker than that of
SDF-1 in that SDF-1 but not RANTES also enhanced proliferation
and IL-2 production by anti-CD3-activated
CD4+ T cells. Therefore, SDF-1 appears to have a
greater potential as a costimulator of peripheral
CD4+ T cells. It is unlikely that the results
reflect the frequency of RANTES ligand expressing peripheral
CD4+ T cells because RANTES can bind to numerous
receptors, including C-C chemokine receptors 1, 3, 5, and 9. Although
previous studies reported that RANTES enhanced IL-2 production and
proliferation by anti-CD3-stimulated peripheral
CD3+ T cells (27), the current data
showed that RANTES did not enhance IL-2 production and proliferation by
anti-CD3-stimulated peripheral CD4+ T cells.
Therefore, it is possible that CD8+ T cells or
T cells are necessary for up-regulation of IL-2 production and
proliferation by RANTES. Recently, it was reported that MIP-3ß
up-regulated IL-10 production by peripheral T cells stimulated with
anti-CD3 and anti-CD28 (29). However, MIP-3ß did
not up-regulate CD69 and CD25 expression. These results suggest that
other chemokines may also have the potential to costimulate T cell
activation, although the pattern of activation may differ for different
chemokine-chemokine receptor interactions.
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Footnotes |
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2 Current address: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892.
3 Address correspondence and reprint requests to Dr. Peter E. Lipsky at the current address: National Institute of Arthritis and Musculoskeletal and Skin Diseases, Building 10, Room 9N228, 10 Center Drive MSC 1820, Bethesda, MD 20892-1820.
4 Abbreviations used in this paper: SDF, stromal cell-derived factor; CXCR, CXC chemokine receptor; MIP, macrophage inflammatory protein.
5 T. Nanki, K. Hayashida, H. J. Girschick, S. Yavuz, and P. E. Lipsky. SDF-1-CXCR4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium. Submitted for publication.
Received for publication December 22, 1999. Accepted for publication March 16, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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associates with heparan sulfates through the first beta-strand of the chemokine. J. Biol. Chem. 274:23916. and stem cell factor/kit ligand share signaling pathways in hemopoietic progenitors: a potential mechanism for cooperative induction of chemotaxis. J. Immunol. 161:3652.-chemokine, stromal cell-derived factor-1, binds to the transmembrane G-protein-coupled CXCR-4 receptor and activates multiple signal transduction pathways. J. Biol. Chem. 273:23169.-induced lymphocyte polarization and chemotaxis. J. Immunol. 163:4001.This article has been cited by other articles:
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M. Ticchioni, C. Charvet, N. Noraz, L. Lamy, M. Steinberg, A. Bernard, and M. Deckert Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration Blood, May 1, 2002; 99(9): 3111 - 3118. [Abstract] [Full Text] [PDF]
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J. H. Dufour, M. Dziejman, M. T. Liu, J. H. Leung, T. E. Lane, and A. D. Luster IFN-{gamma}-Inducible Protein 10 (IP-10; CXCL10)-Deficient Mice Reveal a Role for IP-10 in Effector T Cell Generation and Trafficking J. Immunol., April 1, 2002; 168(7): 3195 - 3204. [Abstract] [Full Text] [PDF]
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S. S. Cheng, N. W. Lukacs, and S. L. Kunkel Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells J. Immunol., March 15, 2002; 168(6): 2887 - 2894. [Abstract] [Full Text] [PDF]
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C. Hernandez-Lopez, A. Varas, R. Sacedon, E. Jimenez, J. J. Munoz, A. G. Zapata, and A. Vicente Stromal cell-derived factor 1/CXCR4 signaling is critical for early human T-cell development Blood, January 15, 2002; 99(2): 546 - 554. [Abstract] [Full Text] [PDF]
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F. Vinante, A. Rigo, M. T. Scupoli, and G. Pizzolo CD30 triggering by agonistic antibodies regulates CXCR4 expression and CXCL12 chemotactic activity in the cell line L540 Blood, January 1, 2002; 99(1): 52 - 60. [Abstract] [Full Text] [PDF]
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R. Tanaka, A. Yoshida, T. Murakami, E. Baba, J. Lichtenfeld, T. Omori, T. Kimura, N. Tsurutani, N. Fujii, Z.-X. Wang, et al. Unique Monoclonal Antibody Recognizing the Third Extracellular Loop of CXCR4 Induces Lymphocyte Agglutination and Enhances Human Immunodeficiency Virus Type 1-Mediated Syncytium Formation and Productive Infection J. Virol., December 1, 2001; 75(23): 11534 - 11543. [Abstract] [Full Text]
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T. Nanki, K. Nagasaka, K. Hayashida, Y. Saita, and N. Miyasaka Chemokines Regulate IL-6 and IL-8 Production by Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis J. Immunol., November 1, 2001; 167(9): 5381 - 5385. [Abstract] [Full Text] [PDF]
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Y. Suzuki, M. Rahman, and H. Mitsuya Diverse Transcriptional Response of CD4+ T Cells to Stromal Cell-Derived Factor (SDF)-1: Cell Survival Promotion and Priming Effects of SDF-1 on CD4+ T Cells J. Immunol., September 15, 2001; 167(6): 3064 - 3073. [Abstract] [Full Text] [PDF]
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N. C. Ottoson, J. T. Pribila, A. S. H. Chan, and Y. Shimizu Cutting Edge: T Cell Migration Regulated by CXCR4 Chemokine Receptor Signaling to ZAP-70 Tyrosine Kinase J. Immunol., August 15, 2001; 167(4): 1857 - 1861. [Abstract] [Full Text] [PDF]
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 R. S. Klein, J. B. Rubin, H. D. Gibson, E. N. DeHaan, X. Alvarez-Hernandez, R. A. Segal, and A. D. Luster SDF-1{alpha} induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells Development, June 1, 2001; 128(11): 1971 - 1981. [Abstract] [Full Text] [PDF]
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 D. Dubois-Laforgue, H. Hendel, S. Caillat-Zucman, J.-F. Zagury, C. Winkler, C. Boitard, and J. Timsit A Common Stromal Cell-Derived Factor-1 Chemokine Gene Variant is Associated With the Early Onset of Type 1 Diabetes Diabetes, May 1, 2001; 50(5): 1211 - 1213. [Abstract] [Full Text]
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J.-W. Oh, K. Drabik, O. Kutsch, C. Choi, A. Tousson, and E. N. Benveniste CXC Chemokine Receptor 4 Expression and Function in Human Astroglioma Cells J. Immunol., February 15, 2001; 166(4): 2695 - 2704. [Abstract] [Full Text] [PDF]
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T. Nanki, K. Hayashida, H. S. El-Gabalawy, S. Suson, K. Shi, H. J. Girschick, S. Yavuz, and P. E. Lipsky Stromal Cell-Derived Factor-1-CXC Chemokine Receptor 4 Interactions Play a Central Role in CD4+ T Cell Accumulation in Rheumatoid Arthritis Synovium J. Immunol., December 1, 2000; 165(11): 6590 - 6598. [Abstract] [Full Text] [PDF]
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