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Departments of Medicine and Microbiology-Immunology, University of California Medical Center, San Francisco, CA 94143
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The T cell tumor lines responsive to S1P and/or LPA express many of the Edg Rs, with predominance of Edg-2, -3, and -4 Rs (11, 12). In contrast to T cells of tumor lines, CD4+ and CD8+ T cells isolated at high purity by immunomagnetic beads from blood of healthy humans have more sharply focused patterns of constitutive expression of Edg Rs, as assessed by semiquantification of mRNA with PCR and of protein using a new set of mAbs for Western blots (14). CD4+ T cells show a vast predominance of Edg-4 LPA Rs, with only occasional traces of Edg-3>-2 or -5 Rs, whereas CD8+ T cells have only traces of Edg-2 and -5 Rs. The generation of IL-2 by CD4+ T cells, but not CD8+ T cells, stimulated through binding of adherent anti-CD3 plus anti-CD28 mAbs was inhibited by 10-10 to 10-6 M LPA and by mouse agonistic anti-Edg-4 R mAb (14).
Activation of human blood-purified CD4+ T cells with mitogenic lectin for 24 h induces expression of Edg-2 Rs while maintaining prominent expression of Edg-4 Rs (15). This codominance of Edg-2 and Edg-4 Rs converts the net effect of LPA on TCR-evoked IL-2 generation from inhibition to enhancement (15). Anti-Edg-2 R mAb enhancement of TCR-evoked IL-2 generation by mitogen-activated CD4+ T cells, expressing Edg-2 plus Edg-4 Rs, contrasts with anti-Edg-4 R mAb inhibition of TCR-evoked IL-2 generation by newly isolated CD4+ T cells expressing only Edg-4 Rs (14, 15). These findings raised the possibility that Edg-2 and Edg-4 LPA Rs may transduce opposing signals for some T cell functions, but could not definitively establish the role of Edg-2 Rs alone given the concurrent expression of Edg-4 Rs. No known developmental stage or functional state of T cells is characterized by sole or vast predominance of expression of Edg-2 Rs.
Two distinct types of Jurkat-T cell transfectants thus were designed, which, respectively, express predominantly Edg-2 (Jurkat-T-2) and Edg-4 (Jurkat-T-4) Rs. The results of analyses of trans-Matrigel (Collaborative Research, Bedford, MA) migration of the Jurkat-T cell transfectants to LPA and anti-Edg-2 and Edg-4 R Abs confirmed that opposite responses are mediated by Edg-2 and Edg-4 Rs, including motility and recruitment of matrix metalloproteinase (MMP) activity (16).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Jurkat leukemic T cells with the SV40 virus large T Ag (Jurkat-T cells) were obtained from Dr. G. Crabtree (Stanford University, Stanford, CA) and cultured at 0.5–2.0 x 106 per ml in RPMI 1640 medium containing 100 U/ml penicillin, 100 µg/ml streptomycin, and 10% heat-treated FBS at 37°C in 5% CO2. Jurkat-T-2 cells (expressing predominantly Edg-2 Rs), Jurkat-T-4 cells (expressing predominantly Edg-4 Rs), and Jurkat-T-3 cells (expressing predominantly Edg-3 Rs and serving as occasional controls for Jurkat-T-2 and -4 cells) were generated as described for Jurkat and other human T cell lines (17, 18) by Superfect (Qiagen, Chatsworth, CA) lipotransfection with the respective encoding cDNA in a high-expression vector along with the Rep4 hygromycin resistance plasmid and expression plasmids with antisense-encoding cDNAs for the other Edg Rs of Jurkat-T cells. The sense Edg-2/EF3, Edg-3/EF3, and Edg-4/EF3 plasmids and antisense Edg-2/pRc/CMV2, Edg-3/pcDNA 3.1, Edg-4/pcDNA 3.1, and Edg-5/pSV.SPORT 1 plasmids also have been described (11, 12, 18). Thus Jurkat-T-2 cells were derived by lipotransfection of 8 x 106 Jurkat-T cells in 4 ml of RPMI 1640/5% FBS with 2 µg Edg-2/EF3, 4 µg each of antisense Edg-3, -4, and -5 plasmids, and 0.2 µg of Rep4 plasmid, incubated 48 h, washed, and resuspended in 10 ml RPMI 1640/10% FBS with 150 µg/ml (4 days), 300 µg/ml (3 days), and 600 µg/ml (3–9 days) hygromycin for 10–16 days of selection before studies of R expression and migration. Jurkat-T-4 cells were derived similarly by lipotransfection with sense Edg-4/EF3 and a mixture of Edg-2/pRc/CMV2, Edg-3/pcDNA 3.1, and Edg-5/pSV.SPORT 1 antisense plasmids, and Jurkat-T-3 by lipotransfection with sense Edg-3/EF3 and a mixture of Edg-2/pRc/CMV2, Edg-4/pcDNA 3.1, and Edg-5/pSV.SPORT 1 antisense plasmids followed by hygromycin selection for 10–16 days.
RT-PCR semiquantification of mRNA encoding Edg Rs
Total cellular RNA was extracted by the TRIzol method (Life
Technologies, Grand Island, NY) from suspensions of Jurkat-T,
Jurkat-T-2, Jurkat-T-3, and Jurkat-T-4 cells, and four different lines
of rat HTC4 hepatoma cells, which have very low endogenous expression
of native rat Edg-Rs and stably overexpress recombinant human Edg-2,
-3, -4, or -5 Rs (11, 12, 18). RT-PCR was performed as
described (12, 14, 19).
[
-32P]dCTP (2 µCi) was added to some sets
of reaction mixtures to allow radioactive quantification of mRNA
encoding each Edg R relative to that of the constitutive standard G3PDH
(12, 14, 19). The sequences of oligonucleotide primer
pairs for G3PDH and human Edg-1 to -5 and -7 have been provided
(14). Ethidium bromide-stained G3PDH and Edg R cDNA bands
were cut from 2% agarose gels and solubilized in 0.5 ml sodium
perchlorate solution at 55°C for 1 h before beta-scintillation
counting (Elu-Quick; Schleicher & Schuell, Keene, NH). Relative
quantities of cDNA encoding each Edg R were expressed in terms of the
ratio of radioactivity to that in the corresponding G3PDH band
(12, 14, 19).
Western blot analyses of Edg Rs
Proteins were extracted from replicate suspensions of 3–5 x 106 Jurkat-T cells, Jurkat-T-Edg R cells, and HTC4 cell Edg-2, -3, -4, and -5 R stable transfectants, and resolved by electrophoresis along with a rainbow-prestained set of m.w. markers (New England Nuclear, Boston, MA or Amersham, Arlington Heights, IL) as described (12, 15). Blots were developed with 0.3–1 µg/ml mouse monoclonal anti-Edg-2, -3, -4, or -5 R Ab (Antibody Solutions, Palo Alto, CA) and then HRP-labeled goat anti-mouse IgG, before development with an ECL kit (Amersham) (11, 12, 19). The amino-terminal peptide epitopes for Edg-2, -3, -4, and -5 Rs were aa 6–25, 1–21, 9–27, and 1–23, respectively.
Assessment of migration of Jurkat-T cells and blood CD4+ T cells through a model basement membrane
CD4+ T cells were isolated from heparinized venous blood of healthy volunteers using immunomagnetic retention chromatography after incubation with biotinylated mouse monoclonal anti-human CD4+ Abs and streptavidin metallic microbeads (Miltenyi Biotec, Auburn, CA), as described (14). Jurkat-T cells and CD4+ T cells were washed twice and resuspended at 5 x 106/ml in Iscove’s medium with 100 U/ml penicillin, 100 µg/ml streptomycin (University of California at San Francisco Cell Culture Facility), and 50 µg/ml fatty acid-free human serum albumin (Sigma, St. Louis, MO). Replicate 0.2-ml suspensions of Jurkat-T cells and CD4+ T cells were added to the 6.5-mm-diameter inserts of Transwell chambers (Costar, Cambridge, MA) over 8-µm pore width polycarbonate filters (Nucleopore, Pleasanton, CA), which separated the cells from 500 µl medium in the lower compartment, as described (20, 21). The filters were coated continuously and evenly with 15 µl growth factor-depleted Matrigel (20, 21). A stimulus of 10-11 to 10-6 M LPA, S1P, or the control lysophospholipids phosphatidic acid and phosphatidylethanolamine (Biomol, Plymouth Meeting, PA), an anti-Edg R mAb, or RANTES (PeproTech, Rocky Hill, NJ) was introduced only into the lower chamber to establish a concentration gradient for chemotaxis or into the lower and upper chambers without a gradient for chemokinesis. In some studies of intrinsic mobility alone, filters were not coated with Matrigel. Chambers were incubated at 37°C in 5% CO2 in air for the known optimal times of 4 h without Matrigel and 42 h with Matrigel. Inserts then were shaken in the medium of the lower chamber for 5 min to detach cells adherent to the lower surface of filters, and cells in this medium were counted microscopically. Migration responses are expressed as a percentage of the total number of Jurkat-T cells or CD4+ T cells added to the chamber or as a percentage of the control value (100%) in the absence of an inhibitor or enhancer. The hydroxamic acid dipeptide analog inhibitor of MMPs, HONHCO-CH2CH(i-BuCO-L-Trp-methylamide (GM6001) and the inactive control GM2454 were added to the cells and lower compartment medium at 10-8 to 10-6 M.
Quantification of functional MMP activity of Jurkat T cells
To determine the effective level of MMP activity during Jurkat-T migration though Matrigel, 0.1 µg (1.6–1.7 x 105 dpm) of 3H-labeled type IV human collagen (N-[propionate-2, 3-[3H]; 1.08 µCi/µg; New England Nuclear) was mixed thoroughly with each 15 µl Matrigel before coating each filter. The fatty acid-free human serum albumin in migration medium was replaced with MMP-neutral 1% Nutridoma-SP (Boehringer Mannheim, Indianapolis, IN). Replicate aliquots of 30 µl were removed from the lower compartment of each chamber, as well as control chambers without stimuli and without cells, after 4 and 24 h for assessment of fluid phase radioactivity (21). The activity inhibited by 10-5 M GM6001 was attributed to specific in situ MMP.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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),
and not Edg-1 or -7 Rs (data not shown). Radio-PCR semiquantification
of mRNA encoding Edg Rs in untransfected Jurkat-T cells revealed an
approximate rank-order of expression of Edg-3>Edg-2>Edg-4 (Table I). Transfection and selection led to
stabilization of three distinct sets of Jurkat-T cells, which express
almost exclusively mRNA encoding the respective Edg-2 and Edg-4 LPA Rs,
and the Edg-3 S1P R (Fig. 1). The Edg-2 R (Jurkat-T-2)- and Edg-4 R
(Jurkat-T-4)-predominant sets were selected for further studies to
permit analyses of Edg R-dependent determinants of T cell responses to
LPA. The Jurkat T-3 cells were used as controls expressing no
detectable LPA receptor mRNA. Radio-PCR semiquantification of Edg R
mRNA profiles in Jurkat-T-2 and Jurkat-T-4 cells demonstrated
predominance of the expected major Edg R in each set (Table I).
Jurkat-T-2 cells had no Edg-4 R, and Jurkat-T-4 cells had no Edg-2 R.
However, there was slight retention of mRNA for S1P Edg Rs, especially
Edg-3R. Western blot studies of Edg R protein expression in the
Jurkat-T cell transfectants confirmed the results of analyses of mRNA.
Each set of transfectants expressed predominantly the protein Ag of the
major Edg R, and none expressed Edg-5 R (Fig. 2). Jurkat-T-2 cells also contain a low
level of Edg-3 R but, importantly, had no Edg-4 R, and Jurkat-T-4 cells
have low levels of Edg-3 R but only a trace of Edg-2 R Ag.
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). LPA stimulated trans-Matrigel
migration of Jurkat-T-4 cells significantly at
10-9 M and maximally at
10-7 M to a level >4-fold higher than the
baseline of unstimulated migration, whereas S1P elicited significant,
but lesser, migration only at 10-6 M. As equal
concentrations of LPA on both sides of the micropore filter evoked
Jurkat-T-4 cell migration of the same magnitude as an identical
concentration of LPA only in the stimulus compartment, chemokinesis
appears to be the major mechanism. Jurkat-T-2 and Jurkat-T-3 cells
responded only marginally to the highest concentration of LPA. The
specificity controls dioleoylphosphatidic acid and
phosphatidylethanolamine had no effects on migration of Jurkat-T-2 or
Jurkat-T-4 cells.
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and III). The level of chemotaxis was
dependent on anti-Edg-4 R mAb concentration and attained a maximal
increment similar to that for LPA. Anti-Edg-2 R mAb specific for a
substituent peptide in the extracellular amino terminus of Edg-2 R
failed to induce significant trans-Matrigel migration of Jurkat-T-2 or
Jurkat-T-4 cells. Neither LPA nor mAbs affected migration of
Jurkat-T-3 cells. Mitogen-activated human blood
CD4+ T cells express both Edg-2 and Edg-4 Rs
(15). The anti-Edg-4 R mAb, but not the anti-Edg-2
R mAb, elicited trans-Matrigel chemotactic responses of activated
CD4+ T cells (Table IV). The chemotactic responses of
activated CD4+ T cells attained a maximum level
similar to that evoked by RANTES (Table IV).
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). LPA suppressed significantly
the trans-Matrigel migration of Jurkat-T-2 cells elicited by
RANTES with LPA concentration dependence. In contrast, LPA
increased slightly RANTES-induced migration of Jurkat-T-4 cells with
less than additive total responses (Fig. 4). For activated
CD4+ T cells expressing Edg-2 and Edg-4 Rs,
anti-Edg-2 R mAb suppressed the chemotactic response to RANTES with
mAb concentration dependence, whereas anti-Edg-4 R mAb increased
significantly, but less than additively, the net chemotactic response
to RANTES (Table V).
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A).
MMP activity was increased similarly for the two stimuli up to levels
4-fold higher than the baseline. In contrast, the same stimuli had no
effect on MMP activity of Jurkat-T-2 cells. RANTES enhanced MMP
activity in Jurkat-T-2 and Jurkat-T-4 cells by a range of 2.3- to
4.7-fold. LPA and anti-Edg-2 R mAb both suppressed significantly
RANTES-elevated MMP activity of Jurkat-T-2 cells (Fig. 5B).
In contrast, both LPA and anti-Edg-4 R mAb, but not
anti-Edg-2 R mAb, further increased RANTES-elevated MMP activity of
Jurkat-T-4 cells (Fig. 5B). At the higher concentration of
each stimulus used, the total increase in in situ MMP activity of
Jurkat-T-4 cells was more than additive of the separate responses to
RANTES and LPA or anti-Edg-4 R mAb (Fig. 5B). Neither
LPA nor mAbs affected MMP activity of Jurkat-T-3 cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2, and Table I). Analyses of migration
and related responses of the Jurkat-T-2 and Jurkat-T-4 transfectants to
LPA and agonist anti-Edg R mAbs permitted definition of some
functional differences between Edg-2 and -4 Rs. This had not been
possible in human blood T cells because there is no known developmental
stage or functional state in which Edg-2 Rs are expressed alone or with
sufficient predominance (14, 15).
The distinctive role of each LPA-specific Edg R in T cells was
demonstrated in the trans-Matrigel model of migration across a
simulated basement membrane. LPA, but not S1P, enhanced trans-Matrigel
migration of Jurkat-T-4 cells, but not Jurkat-T-2 cells (Fig. 3).
Transduction of stimulation of T cell migration by Edg-4 Rs, but not
Edg-2 Rs, was confirmed by applying anti-Edg R-selective mAbs in
the same assay system. Anti-Edg-4 R mAb evoked trans-Matrigel migration
of Jurkat-T-4 cells, but not Jurkat-T-2 cells, whereas anti-Edg-2 R
Ab had no stimulatory effect on migration of either type of Jurkat
transfectant (Tables II and III). The differential effects of
anti-Edg R Abs also was observed with human blood
CD4+ T cells after mitogen activation, which
results in codominant expression of both Edg-2 and Edg-4 Rs (14, 15). Anti-Edg-4 R mAb, but not anti-Edg-2 R mAb, elicited
chemotaxis of mitogen-activated CD4+ T cells
(Table IV). That LPA-elicited migration appears to be principally
chemokinesis and that elicited by anti-Edg-4 R Ab largely
chemotaxis, may reflect only differences in the physicochemical
properties of the two stimuli (Fig. 3, Tables II and III). Peptides and
proteins readily establish a concentration gradient across a micropore
filter, but the amphipathic phospholipids adhere to numerous surfaces
including micropore filters, which may diminish effective
concentrations in the cellular compartment.
Instead of transducing an LPA signal stimulatory to T cell migration,
Edg-2 Rs inhibit responses to the chemokine RANTES in settings where
the Edg-4 R has an enhancing effect (Fig. 4). The same effect was
observed with mitogen-activated CD4+ T cells,
where anti-Edg-2 R mAb, but not anti-Edg-4 R mAb, suppressed
RANTES-induced chemotaxis (Table V). As Edg-2 Rs did not suppress
spontaneous migration of Jurkat-T cell transfectants or
mitogen-activated CD4+ T cells, it seemed
possible that the observed inhibition of stimulated trans-Matrigel
migration might be attributable to a negative effect on a
critical component of the response other than intrinsic motility. One
striking effect of many factors that enhance T cell migration is
augmentation of MMP activity, which is predominantly due to increases
in secretion of activated MMP-9 (21, 22). A functional
assay for enhanced activity of the gelatinase-type MMPs on or
near migrating T cells is quantification of release of degraded
fragments from human type IV [3H]collagen
suspended in the Matrigel above filters. In this assay, LPA and
anti-Edg-4 R mAb, but not anti-Edg-2 R mAb, stimulated MMP
functional activity of Jurkat-T-4 cells during trans-Matrigel
migration, without affecting Jurkat-T-2 cell MMP activity (Fig. 5A). Migration-enhancing concentrations of RANTES also
stimulated MMP in situ activity of Jurkat T-2 and Jurkat-T-4 cells
(Fig. 5B). MMP activity of Jurkat-T-2 cells was inhibited
significantly by LPA and anti-Edg-2 R mAb, but not anti-Edg-4 R
mAb. Under the same conditions, LPA and anti-Edg-4 R mAb, but not
anti-Edg-2 mAb, increased more than additively RANTES-evoked
migration of Jurkat-T-4 cells (Fig. 5B).
Transduction of opposite signals from LPA by Edg-2 and -4 Rs thus has been documented with respect to two different functions of T cells. TCR-dependent stimulation of generation and secretion of IL-2 by Jurkat T cells and human blood-derived CD4+ T cells is suppressed by Edg-4 R-transduced signals from LPA and by anti-Edg-4 R mAb (14, 15). In the same setting, Edg-2 R-transduced signals from LPA and anti-Edg-2 R mAb enhance IL-2 release (15). Regulation of trans-Matrigel migration of T cells by Edg-2 Rs and -4 Rs now is observed to be the inverse of that documented for IL-2 secretion (14, 15). Edg-4 R signals enhance and Edg-2 R signals inhibit trans-Matrigel migration and the related function of release of endogenous MMP. Such results strengthen the hypothesis that LPA-evoked responses of activated native T cells bearing both LPA Edg Rs are the summation of separate signals from Edg-2 and Edg-4 Rs. Integration of these findings suggests that contributions of LPA in recruitment and immunostimulation of T cells differ with their state of activation. The Edg-4 Rs that predominate on unactivated blood CD4+ T cells signal amplification of MMP-dependent migration across basement membranes and into sites of immune responses, while suppressing secretion of IL-2 and possibly other cytokines. After T cells are activated by Ag, Edg-2 R expression is up-regulated, and signaling would shift partially to inhibition of responses of MMP-dependent migration to chemokines and other chemotactic factors, localizing the T cells at the site of the immune response, while enhancing generation of IL-2 and possibly other cytokines. Thus in both the recruitment and effector phases of the immune responses of helper T cells, LPA has complex facilitatory functional roles. Much additional data will be required to support or modify this tentative formulation of the contributions of LPA in immunity.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Edward J. Goetzl, University of California, UB8B, Box 0711, 533 Parnassus at 4th, San Francisco, CA 94143-0711.
3 Abbreviations used in this paper: LPA, lysophosphatidic acid; S1P, sphingosine 1-phosphate; Edg R, G protein-coupled receptor encoded by an endothelial differentiation gene; MMP, matrix metalloproteinase; Jurkat-T-2, Edg-2 R-predominant transfectant of Jurkat T cell; Jurkat-T-4, Edg-4 R-predominant transfectant of Jurkat T cell.
Received for publication July 25, 2000. Accepted for publication November 27, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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