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Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells

Departments of Medicine and Microbiology, University of California, San Francisco, California, USA

¹Correspondence: University of California, UB8B, UC Box 0711, 533 Parnassus at 4th, San Francisco, CA 94143-0711, USA. E-mail: egoetzl{at}itsa.ucsf.edu

	ABSTRACT

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Sphingosine 1-phosphate (S1P) from platelets and macrophages stimulates migration and enhances survival of T cells. Mouse spleen CD4 and CD8 T cells are shown to express predominantly S1P₁ (Edg-1) and S1P₄ (Edg-6) G-protein-coupled receptors with only minimal representation of S1P₂, S1P₃, and S1P₅. At and below plasma concentrations of healthy mammals (1 nM–1 µM), S1P evokes trans-Matrigel chemotaxis of mouse CD4 and CD8 T cells and recruits T cells into subcutaneous air pouches. T cell receptor-mediated activation of CD4 T cells suppresses expression of S1P₁ and S1P₄ receptors and eliminates their chemotactic responses to S1P. The immunoregulator FTY720, a structural homologue of S1P, lacks T cell chemotactic activity and competitively inhibits T cell chemotactic responses to S1P in vitro and in vivo. S1P may be a distinctive contributor to compartmental immunity by attracting naïve and memory T cells preferentially over activated effector T cells.—Graeler, M., Goetzl, E. J. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells.

Key Words: immunity • chemokine • lysophospholipid • receptor • G-protein

	INTRODUCTION

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THE LYSOPHOSPHOLIPID GROWTH factors sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are generated predominantly by stimulated platelets and leukocytes, resulting in up to micromolar concentrations in normal plasma and some other extracellular fluids (1 2 3) . S1P and LPA evoke cellular proliferation and diverse functional responses by binding to members of a family of homologous G-protein-coupled receptors, originally designated endothelial differentiation gene-encoded or Edg receptors (4 5 6) . Recently, a Subcommittee of the International Union of Pharmacologists has renamed these receptors for their principal ligand and order of discovery, so the LPA receptors are LPA₁ (Edg-2), LPA₂ (Edg-4), and LPA₃ (Edg-7) and the S1P receptors are S1P₁ (Edg-1), S1P₂ (Edg-5), S1P₃ (Edg-3), S1P₄ (Edg-6), and S1P₅ (Edg-8).

Blood CD4 T cells express LPA₂ receptors constitutively whereas unstimulated CD8 T cells show only traces of LPA₁ (7) . Mitogen activation of human CD4 T cells down-regulated expression of LPA₂ and up-regulated that of LPA₁, but such activation of human CD8 T cells did not alter expression of any LPA receptor (8) . LPA₂ transduced LPA suppression and LPA₁ mediated LPA enhancement of IL-2 production/secretion by CD4 T cells. In contrast, LPA₂ transduced LPA-evoked chemotaxis and chemokinesis of CD4 T cells whereas LPA₁ failed to signal migration directly, but mediated LPA suppression of chemokine-elicited chemotaxis of CD4 T cells (9) . Thus, the effects of activation of CD4 T cells on LPA receptors converted LPA from a migration-enhancing and cytokine-inhibiting factor to a migration-inhibiting and cytokine-enhancing factor. In the course of studies of T cell LPA receptors, S1P was noted to elicit T cell chemotactic responses (9) . The goal of the present investigation is to define patterns of expression of S1P receptors by subsets of mouse splenic T cells and elucidate mechanisms of transduction of the functional effects of S1P on T cells.

	MATERIALS AND METHODS

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Isolation and activation of mouse spleen CD4 and CD8 T cells
Mouse CD4 and CD8 T cells were isolated from splenocytes of 6- to 8-wk-old C57BL/6 female mice at a minimum purity of 97% using metallic beads bearing anti-CD4 and anti-CD8 MoAbs, respectively, and two cycles of magnetic retention chromatography (Miltenyi-Biotec, Auburn, CA), as described (7 , 8) . Suspensions (1 mL) of purified T cells in RPMI-50 µg/mL of fatty acid-free BSA (FAF-BSA) (Calbiochem, La Jolla, CA) were activated by incubation for 24 h on 2 µg each of adherent anti-CD3 + anti-CD28 MoAbs (PharMingen, San Diego, CA) in 6-well plates.

Real-time PCR quantification of mRNA encoding S1P G-protein-coupled receptors
Total RNA was isolated with TRIzol (Life Technologies, Grand Island, NY), treated with DNase I, and amplified quantitatively in 50 ng replicates with TaqMan primers and probes for mouse S1P receptors and the constitutive standard glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Integrated DNA Technologies, Coralville, IA). Analyses were conducted in the Prism 7700 Sequence Detection System with the recommended optimal reagents and conditions providing interanalysis coefficients of variation <4% (PE Applied Biosystems, Foster City, CA). The value of each unknown was determined by a standard threshold cycle method using GAPDH as the reference sequence and a calibration curve derived from known amounts of RNA.

Western blot analyses of S1P receptors
Immunoblots of proteins extracted from 5 x 10⁶ T cells and HTC4 cell transfectants stably expressing S1P₁ or S1P₄ receptors were generated as described (8) and developed with rabbit anti-S1P₁ Ab and mouse anti-S1P₄ MoAb (ExAlpha, Boston, MA).

Quantification of mouse T cell trans-Matrigel chemotaxis and HTC4 cell chemokinesis
Migration of mouse purified T cells was analyzed in Transwell chambers (Costar, Cambridge, MA) with 8 µm pore width polycarbonate filters, as described (10) , except that the layer of growth factor-depleted Matrigel was reduced from 15 µL to 8 µL, T cell suspensions were 1 x 10⁷/mL, and CCL21 (Exodus-2) chemokine (Peprotech, Rocky Hill, NJ) was the positive control. In selected assays of intrinsic mobility without a model membrane, 5 µm pore filters lacked Matrigel and were instead coated with 8 µL of a 0.05 µg/mL solution of type IV collagen (Sigma, St. Louis, MO); migration was for 6 h. HTC4 rat hepatoma cells, which lack endogenous S1P receptors, were transfected with human S1P₁ and S1P₄ receptors (as reviewed in ref 5 ). Migration of HTC4 transfectants was studied in Transwell chambers with type IV collagen-coated 8 µm pore width polycarbonate filters and migration was for 24 h. FTY720 was supplied by Dr. Tetsuro Fujita (Kyoto, Japan) and used at 1 nM to 1 µM either in the stimulus compartment alone as a chemotactic factor or at the same concentration in the stimulus and T cell compartments as a chemokinetic factor. The significance of differences between altered and control migration in both these chambers and the in vivo model was calculated with a two-sample t test.

Assessment of mouse lymphocyte recruitment to dorsal s.c. air pouches
Air pouches were established on the back of each mouse by s.c. injection of 5 mL of micropore-filtered air. Two days later, pouch airspaces were irrigated twice with 1 mL of PBS, then received 0.2 mL of PBS-50 µg/mL FAF-BSA alone as a control or with 1 µM S1P and/or 1 µM FTY720. Pouch cells were harvested in 1 mL of PBS at 24 and 48 h, and pouch spaces were rechallenged with S1P and/or FTY720 after the 24 h wash. With a 1 µM S1P challenge, lymphocytes constituted >70% and >80%, respectively, of the total leukocytes at 24 and 48 h.

	RESULTS

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Freshly isolated mouse CD4 T cells contain mRNA encoding S1P₁ (Edg-1) and S1P₄ (Edg-6) receptors, with only minimal representation of S1P₂, S1P₃, and S1P₅ receptors (Table 1 ). T cell receptor-directed stimulation of the CD4 T cells with anti-CD3 plus anti-CD28 MoAbs significantly suppressed S1P₁ and S1P₄ mRNA levels. Immunoblots of the S1P receptors in unstimulated CD4 T cells showed strong bands for S1P₁ and S1P₄ (Fig. 1 ) but no detectable S1P₂, S1P₃, or S1P₅ receptors. Stimulation of the CD4 T cells resulted in loss of detectable S1P₁ and S1P₄ receptor protein (Fig. 1) . The relative representation of S1P receptors was the same in purified CD8 T cells as CD4 T cells, with S1P₁ and S1P₄ most prominent and T cell receptor-directed stimulation similarly suppressing their expression.

View larger version (43K): [in this window] [in a new window]   Figure 1. Western blots of S1P receptors extracted from mouse splenic CD4 cells before (A) and after (B) activation by 24 h of incubation on adherent anti-CD3 plus anti-CD28 antibodies. 2 µg of cellular proteins from HTC4 cell standard transfectants (C) expressing recombinant Edg-1 and Edg-6, respectively, and 10 µg from unstimulated CD4 T cells (Tu) and from activated CD4 T cells (Ts) were resolved and stained with rabbit anti-Edg-1 and mouse monoclonal anti-Edg-6 antibodies. Horizontal lines at the left margin of each frame denote the position of 62 kDa and 51 kDa prestained protein markers.

Trans-Matrigel migration of CD4 T cells was stimulated chemotactically by S1P with significant increases at 10^-9 M and maximal responses at 10^-7 M (Fig. 2 ). Modest apparent chemokinetic responses evoked by an equal concentration of S1P on both sides of the filter were significantly less than chemotaxis at 10^-8 M S1P and absent at 10^-6 M S1P. The pattern of chemotactic and minor chemokinetic responses of CD8 T cells elicited by S1P was the same as that of CD4 T cells, as expected from their similar levels of expression of S1P₁ and S1P₄ receptors (Fig. 2) . The results were essentially identical for more rapid migration of CD4 T cells through type IV collagen-coated filters without Matrigel. S1P at 10^-9 M, 10^-8 M, 10^-7 M, and 10^-6 M, respectively, stimulated chemotaxis of 9.4 ± 0.6%, 17 ± 0.7%, 24 ± 1.2%, and 16 ± 1.0% (mean±SD, n=3) of the initial CD4 T cells compared with the background of 4.6 + 0.9%. T cell receptor-directed activation of CD4 T cells, which was shown to down-regulate S1P receptors, also eliminated their trans-Matrigel chemotactic responses to S1P while increasing significantly chemotaxis elicited by CCL21 (Fig. 3 ) and similarly inhibiting chemotaxis evoked by 10^-8 M to 10^-6 M LPA. To begin to delineate individual contributions of the S1P₁ and S1P₄ receptors, two sets of HTC4 cell transfectants that respectively express solely S1P₁ or S1P₄ were examined for their migration responses to S1P (Fig. 4 ). Only the S1P₁ transfectants responded to S1P and showed a chemokinetic pattern of migration clearly distinguishable from the chemotactic responses of T cells (Fig. 2) . Analysis of the S1P concentration dependence of HTC4-S1P₁ cell chemokinesis revealed significance at 10^-8 M, a peak at 10^-7 M, and a less than maximal response at 10^-6 M (Fig. 4) .

View larger version (30K): [in this window] [in a new window]   Figure 2. Trans-Matrigel chemotactic activity of S1P for mouse splenic CD4 and CD8 T cells. Each bar and symbol of variation depicts the mean ± SD of the results of 3 studies conducted in duplicate. The open (right-hand) bar of each pair at 10-8 M and 10-6 M S1P shows the chemokinetic response to equal concentrations of S1P in the 0.2 mL suspension of 2 x 106 T cells in the upper chamber and the 0.6 mL of medium in the lower chamber. Statistical significance of the difference between each mean value and the mean for medium alone (extreme left-hand bar in each set) was determined by a two-sample t test and depicted as +P < 0.05 and *P < 0. 01.

View larger version (19K): [in this window] [in a new window]   Figure 3. T cell receptor activation-induced suppression of chemotactic responses of CD4 T cells to S1P. Depiction of results (n=3) and analyses of statistical significance are the same as in Fig. 2 . The responses to the chemokine CCL-21 (Exodus-2) are increased by TCR activation.

View larger version (29K): [in this window] [in a new window]   Figure 4. S1P stimulation of migration of HTC4 cell transfectants expressing human S1P1 or S1P4 receptors. The depictions of results (n=3) and analyses of statistical significance are the same as in Fig. 2 .

FTY720 is an immunomodulatory drug known to be effective in prevention of allograft rejection and is structurally homologous to S1P (Fig. 5 ,insert) (11) . At least part of the activity of FTY720 is attributable to reversible suppression of circulating lymphocyte levels and lymphocyte recruitment to diverse grafted organs as a result of their sequestration in secondary lymphoid organs (12) . Recent data from in vivo studies suggested that S1P and a phosphoryl derivative of FTY720 trap lymphocytes in lymph nodes by acting as agonists at several S1P receptors (13) . However, our direct in vitro assessment of concentrations of FTY720 that lymphocytes are known to convert to the phosphoryl derivative of FTY720 failed to reveal stimulation of mouse CD4 T cell trans-Matrigel migration. With a background level of 3.9% ± 0.9% migration, 10^-9 M to 10^-7 M FTY720 did not stimulate either chemotactic or chemokinetic responses of CD4 T cells over 6–60 h. The highest level of chemotactic migration of 7.2% ± 1.9% for 10^-8 M FTY720 at 36 h was not significantly different from the background. However, FTY720 did effectively inhibit the chemotactic responses of CD4 T cells to S1P (Fig. 5) . With 10^-8 M and 10^-7 M S1P as a chemotactic stimulus, inhibition by FTY720 was significant from molar ratios of 0.1 to 10, and equimolar levels of FTY720 inhibited the chemotactic effect of both concentrations of S1P by 50%. In contrast, FTY720 did not inhibit chemotactic responses to LPA. This inhibitory activity of FTY720 was also observed in vivo in an s.c. air pouch model. Introduction of a solution of 1 µM S1P into the air pouch evoked significant influx of mononuclear leukocytes at 24 and 48 h, of which >50% were CD4 T cells by flow cytometry. FTY720 had no direct stimulatory effect in this model but significantly inhibited lymphocyte responses to S1P (Fig. 6 ). These data imply that the in vivo sequestration of lymphocytes by FTY720 and possibly its phosphoryl metabolite are not attributable to a direct chemotactic effect.

View larger version (19K): [in this window] [in a new window]   Figure 5. Inhibition by FTY720 of S1P-evoked trans-Matrigel chemotaxis of CD4 T cells. The depictions of results (n=3) are the same as in Fig. 2 . Representations of the statistical significance of the decreases relative to controls without FTY720 use the same symbols as in Fig. 2 . The insert presents structures of FTY720, without and with the phosphate ester, and S1P.

View larger version (17K): [in this window] [in a new window]   Figure 6. Recruitment of T cells into mouse dorsal s.c. air pouches by S1P. Each bar and symbol of variation depicts the mean ± SD for two groups of two 6- to 8-wk-old C57BL/6 mice. Values on the ordinate are total number of mononuclear leukocytes recovered in a 1 mL saline lavage of each air pouch at 24 h (cross-hatched bar) and 48 h (open bar). Symbols for statistical significance of the differences in mononuclear leukocyte counts between those evoked by S1P, FTY720, or both compared with saline alone are the same as in Fig. 2 .

	DISCUSSION

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S1P thus is a potent lymphocyte chemotactic factor capable of stimulating T cell migration across a model basement membrane in vitro and into s.c. tissue sites at concentrations below and equal to those present physiologically in plasma (Figs. 2 and 6 ). The T cell response to S1P is dependent on full expression of S1P₁ and/or S1P₄ receptors, as activation of the T cells that suppresses expression of these S1P receptors concomitantly eliminates T cell chemotactic responses to S1P (Table 1 , Fig. 3 ). The migratory responses of HTC4-S1P₁ transfectants, but not HTC4-S1P₄ transfectants, to S1P suggested that the S1P₁ receptor of T cells is the principal transducer of chemotactic responses to S1P. However, differences in the type of migratory response and potential differences in the signaling machinery of the two cell types suggest the importance of further investigation of this point.

Concentrations of FTY720 capable of inhibiting lymphocyte recirculation and recruitment into allografts by preventing their egress from secondary lymphoid organs lack lymphocyte direct chemotactic activity but suppress lymphocyte chemotactic responses to S1P in vitro and in vivo (Figs. 5 and 6 ). This suggests that one action of FTY720 on lymphocyte movement in lymphoid and nonlymphoid tissues may be suppression of the stimulatory effects of S1P and possibly other lysophospholipids on migration. It is expected that such effects would be expressed preferentially on naïve and central memory T cells with high levels of S1P₁ and S1P₄ receptors, rather than activated effector T cells that have reduced or no expression of S1P receptors.

There is an apparent contradiction between our findings for T cell migration and those of recent studies of lymphocyte trafficking, which suggest that a phosphoryl metabolite of FTY720 mimics S1P as an S1P receptor agonist and trapping factor for lymphocytes (13 , 14) . Reconciliation of these differences will require detailed investigations of at least several points: 1) the extent of phosphorylation of FTY720 in vivo during a usual therapeutic course; 2) the effects of phosphorylated FTY720 on T cell migration and other T cell functions; and 3) the recirculation behavior of lymph node lymphocytes and/or the in vivo chemotactic responses of T cells after exposure to levels of FTY720 found in plasma during a therapeutic course and/or to physiological concentrations of S1P, rather than to the much higher levels resulting from acute or sustained intravenous infusions (13) . The latter analyses are especially important in view of the lack of effect on circulating lymphocytes of doses of S1P, which did not raise blood levels above the physiological range (14) . The present results justify more comprehensive analyses of the roles of S1P in both trafficking and compartmental mobilization of T cells and other lymphocytes.

	ACKNOWLEDGMENTS

 
This work was supported by National Institutes of Health grant HL-31809.

Received for publication June 10, 2002. Revision received September 4, 2002.

	REFERENCES

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