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The Journal of Immunology, 2006, 177: 7525-7529.
Copyright © 2006 by The American Association of Immunologists, Inc.

CUTTING EDGE

Cutting Edge: Stimulation of Dopamine D4 Receptors Induce T Cell Quiescence by Up-Regulating Krüppel-Like Factor-2 Expression through Inhibition of ERK1/ERK2 Phosphorylation1

Chandrani Sarkar2,*, Shamik Das2,*, Debanjan Chakroborty2,*, Uttio Roy Chowdhury*, Biswarup Basu*, Partha Sarathi Dasgupta3,* and Sujit Basu3,{dagger},{ddagger}

* Signal Transduction and Biogenic Amines Laboratory and {dagger} Department of Medical Oncology, Chittaranjan National Cancer Institute, Kolkata, India; and {ddagger} Mayo Clinic Cancer Center and Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
The neurotransmitter dopamine (DA) is an important regulator of human T cell functions. Although it has been observed that DA, by acting through the D1/D5, D2, and D3 receptors, can activate resting T cells by stimulating the release of cytokines and the expression of surface integrins and also inhibit the proliferation of activated T cells by down-regulating nonreceptor tyrosine kinases, there is not yet a report indicating the functional significance of the D4 DA receptors present in these cells. The present work, for the first time, demonstrates that the stimulation of D4 DA receptors in human T cells induces T cell quiescence by up-regulating lung Krüppel-like factor-2 expression through the inhibition of ERK1/ERK2 phosphorylation. These results reveal a new link between the nervous system and T cell quiescence and indicate that D4 DA receptor agonists may have a therapeutic value in diseases with uncontrolled T cell proliferation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Neural-immune communication is a well-recognized phenomenon (1, 2, 3). It is now well established that the sympathetic nervous system regulates the immune system by releasing neurotransmitters and neuropeptides from the nerve terminals (3). These neurochemicals interact in turn with their specific receptors, including lymphocytes, that are present in different immune effector cells and thereby influence the functional activities of these cells of the host against disease and other environmental stress (1). Among the several neural mediators regulating immune functions, catecholamines play a critical role; within the catecholamine family, Dopamine (DA)4 is of recent interest because different classes of DA receptors (D1/D5, D2, D3, and D4) are present in human T lymphocytes (4). We and others had previously demonstrated that pathophysiological concentrations of DA in vitro inhibited the proliferation of activated T cells and their cytokine secretion by modulating the intracellular signaling pathways that regulate these functions of the cells (4, 5, 6, 7, 8). Also, observations from other laboratories have shown that specific physiological concentrations of DA can even drive the resting human T cells into functional activations through the D2, D3, and D1/D5 classes of DA receptors (9, 10, 11, 12). In addition, the D4 class of DA receptors is present in normal unstimulated human T cells (13). Although recent reports indicate that the D4 DA receptors present in the cardiovascular system and the kidney are associated with blood pressure regulation (14), nothing is known about the functional significance of D4 DA receptors in T lymphocytes. In the present report we have demonstrated that stimulation of the D4 class of DA receptors in human T cells is associated with the expression of Krüppel-like factor (KLF)-2, a critical regulator of quiescence — a state characterized by decreased cell size and metabolic activity of the T cells (15). Recent reports indicate that quiescence in lymphocytes is an actively maintained state rather than a default pathway in the absence of a signal (15, 16, 17). Transcription factors like KLF2 appear to act as master regulators of gene expression patterns that enforce the quiescent phenotype in T cells, and KLF2 is one of the members of the KLF family that bind to GC-rich DNA elements through the conserved DNA-binding zinc finger domain in the C terminus (15). Furthermore, KLF2 is highly expressed in naive T cells, rapidly lost after T cell activation (15), and reestablished in memory T cells, another quiescent population (16, 17).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
T cell stimulation and treatment

T cells, isolated from the blood of healthy donors (approved by the Institutional Review Board of the Chittaranjan National Cancer Institute, Kolkata, India) by using a T cell isolation kit (Miltenyi Biotec), were stimulated with plate-bound anti-CD3 (Sigma-Aldrich) followed by the addition of soluble anti-CD28 (eBioscience) Abs (4 µg/ml each) and 1 x 106 cells together with the specific D4 DA receptor agonist PD 168,077 maleate salt (1 µM; Sigma-Aldrich) or ABT 724 trihydrochloride (1 µM; Tocris Bioscience) at the onset of 48 h of culture. In other experiments, the above-mentioned agonists were added to the T cell culture alone to assess the effects of the agonists on unstimulated T cells. The dosage of the agonists was determined from the dose-response experiments (described in detail in Results and Discussion). To further determine the specificity of the involvement of the D4 class of DA receptors, cells were pretreated with the specific D4 class of DA receptor antagonist U101958 (50 µM; Sigma-Aldrich). Similar experiments were also conducted with the following classes of DA receptor agonists at the specified concentrations as determined from dose-response experiments: D1/D5, SKF38393 (1 µM); D2, quinpirole (2 µM); and D3, PD 128907 (5 µM) (Sigma-Aldrich). In the experiments in which kinase inhibitors were used, T cells were pretreated with vehicle or with the MEK-1/2 inhibitor U0126 (25 µM; Calbiochem), or the p38MAPK inhibitor SB203580 (10 µM; Sigma-Aldrich), or the JNK inhibitor SP600125 (25 µM; Sigma-Aldrich) for 2 h (18, 19) followed by stimulation with anti-CD3 and anti-CD28 in 96-well plates and cultured.

Cell proliferation

A [3H]thymidine incorporation assay was undertaken to measure cell proliferation following anti-CD3/CD28 stimulation (7).

Flow cytometry

Cells were stained with FITC- or PE-conjugated Abs of CD69, CD25 (eBioscience), and 7-aminoactinomycin D (7-AAD) (BD Biosciences). After adjustment with isotype controls, positive cells were enumerated by FACS (FACSCalibur; BD Biosciences) (12).

IL-2 estimation

Culture supernatants were collected from 24-well plates following the stimulation of T cells (1 x 106/ml) with anti-CD3/anti-CD28 in the presence or absence of the D4 agonist PD 168,077 (1 µM) for 24 h at 37°C. Thereafter, the concentration of IL-2 was measured by ELISA using Quantikine ELISA kits (R&D Systems) (7).

Immunoblot analysis for DA D4 receptor, KLF2, and activated MAPK

Proteins from lysed cells were immunoblotted with primary Abs (D4 DA receptor, phospho-ERK1/2, p38 MAPK, and JNK; Santa Cruz Biotechnology) and KLF2 (Imgenex) (7).

RT-PCR analysis of D4 DA receptor and KLF2 mRNA

Total RNA was extracted from isolated T cells following the manufacturer’s protocol (Ambion). Two micrograms of total RNA was reverse transcribed into first strand cDNA by using poly(dT) priming (7) following amplification using a PCR kit (Ambion). The sequences of PCR primers were as follows: D4 DA receptor, 5'-TGCTGTGCTGGACGCCCTTCTTCG-3' (forward) and 5'-CGTTGCGGAACTCGGCGTTGAAGA-3' (reverse) (20); KLF2, 5'-TGCCGTCCTTCTCCACTTTC-3' (forward) and 5'-CTCTTGGTGTAGGTCTTGCC-3' (reverse) (21); 15S rRNA (internal control), 5'-TTCCGCAAGTTCACCTACC-3' (forward) and 5'-CGGGCCGGCCATGCTTTACG-3' (reverse) (7).

Statistical analysis

All data are expressed as the mean ± SEM. Statistical comparisons were performed using Student’s t test. p < 0.05 was considered significant (7).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
D4 DA receptors are expressed in unstimulated human T cells and its stimulation inhibits the proliferation of T cells

RT-PCR and Western blot analysis demonstrated the presence of the D4 class of DA receptors in T cells isolated from normal volunteers (Fig. 1, a and b). Thereafter, when these T cells were treated with the specific D4 DA agonist PD 168,077 (1 µM) at the onset of 48 h of TCR stimulation with anti-CD3/CD28 so that the D4 DA agonist remained throughout this period, these cells showed significant inhibition of T cell proliferation as evident from [3H]thymidine incorporation (Fig. 1c). Treatment with another D4 DA agonist, ABT 724 trihydrochloride (1 µM), also showed similar results (Fig. 1c). Furthermore, to confirm the specificity of the D4 DA receptor-mediated abrogation of anti-CD3/CD28-induced cell proliferation, when these cells were pretreated with U101958, a D4 receptor antagonist, the inhibitory effect of the D4 receptor agonist on T cell proliferation was lost (Fig. 1c). The dosage of D4 receptor agonists used in the present study was determined from the different dose-response (1 nM to 1 mM) effects of the agonists on anti-CD3/CD28-induced T cell proliferation inhibition. From these dose-response studies it was demonstrated that for both of the D4 agonists a concentration of 1 µM was the most effective in inhibiting cell proliferation with negligible cell death (Fig. 1c). In contrast, significant cell death was observed when these agonists were used at concentrations of >6 µM (data not shown). Furthermore because both of the D4 agonists demonstrated a similar inhibition of anti-CD3/CD28-induced cell proliferation, only one D4 agonist, PD 168,077 (1 µM) was used for additional experiments.


Figure 1
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  		FIGURE 1. a and b, RT-PCR (a) and Western blot (b) analysis revealed the presence of the D4 class of dopamine receptors in unstimulated T cells. c, D4 class of dopamine receptor stimulation by different concentrations of its specific agonists PD 168,077 maleate salt and ABT 724 inhibited anti-CD3/CD28-induced proliferation in vitro. Cells (1 x 106) were treated with different concentrations of PD 168,077 maleate salt or ABT 724 simultaneously with anti-CD3/CD28 and cultured for 48 h in complete RPMI 1640 medium in 96-well plates. In other experiments, cells were pretreated with U101958 (50 µM) before treatment with the agonists PD 168,077 and ABT 724 (inset: U, U101958; PD, PD 168,077; St, anti-CD3/CD28 stimulated; ABT, ABT 724) and with CD3/CD28. [3H]Thymidine was added 18 h before the termination of the experiments. d and e, Inhibition of anti-CD3/CD28-induced T cell proliferation in PD 168,077 maleate salt (D4 agonist)-treated cells was not associated with cell death. Cells were treated with a D4 agonist at the onset of stimulation and stained with 7-AAD, and the number of 7-AAD-positive cells was enumerated with flow cytometry (e) and the corresponding dot plots (d). f, D4 receptor agonist treatment inhibited CD3/CD28-induced activation of T cells as evident from the significant reduction of cells characterized by the early activation markers CD69 and CD25. Both D4 agonist-treated and untreated cells with anti-CD3/CD28 stimulation were stained with CD69 and CD25 and analyzed by flow cytometry. Double-positive cells were shown in the upper right quadrant. Results are representative of six separate experiments. In flow cytometry analysis, backgrounds were adjusted with appropriate isotype controls.

 
It should also be noted here that the treatment of unstimulated human T cells with different concentrations of the D4 agonist PD 168,077 (1 nM to 6 µM) alone and without any TCR stimulation had no effect on the proliferation of these cells (Fig. 1c). This result therefore indicates that the dosage of the D4 agonist, which inhibits anti-CD3/CD28-mediated proliferation of stimulated T cells and induces quiescence of these cells, has no effect on unstimulated T cells. Next, to rule out the possibility that the abrogation of anti-CD3/CD28-induced cell proliferation following D4 receptor stimulation by its agonist PD 168,077 was due to cell death, 7-AAD-positive cells were enumerated by flow cytometry. No significant differences were observed between agonist-treated and untreated groups, indicating that the D4 receptor-mediated inhibition of proliferation was not due to the death of the agonist-treated T cells (Fig. 1, d and e).

Inhibition of surface expression of early activation markers on T lymphocytes following the stimulation of D4 DA receptors in these cells

Because proliferation was inhibited without any increase in cell death, the quiescence of these cells was a possibility. Therefore, we first enumerated the surface expression of the early activation markers CD69 and CD25, which, although insignificantly expressed in quiescent T cells, are highly expressed in the activated cells (22). The results demonstrated that T cells stimulated with anti-CD3/CD28 for 24 h robustly expressed surface CD69 and CD25. In contrast, when the anti-CD3/anti-CD28-stimulated T cells were treated with the D4 DA receptor agonist PD 168,077, the expression pattern of these activation markers was similar to that of the resting cells (Fig. 1f).

Stimulation of D4 DA receptors inhibits IL-2 release from anti-CD3/CD28-induced activated T cells

To further confirm that the stimulation of D4 DA receptors in T cells inhibits the induction of T cell activation via a TCR, we next investigated the effect of D4 receptor stimulation on IL-2 secretion by T cells stimulated with anti-CD3/CD28. It was observed that human T cells, when stimulated with anti-CD3/CD28, released IL-2 in the culture. In contrast, when these CD3/CD28-stimulated cells were simultaneously treated with D4 receptor agonist PD 168,077 (1 µM), the IL-2 concentration was similar to that of the unstimulated cells (Fig. 2).


Figure 2
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  		FIGURE 2. Stimulation of D4 DA receptors inhibits IL-2 secretion from anti-CD3/CD28-stimulated T cells in vitro. Cultures were unstimulated, stimulated with anti-CD3/CD28 only, or stimulated with D4 agonist PD 168,077 and anti-CD3/CD28. Results are mean ± SEM of six separate experiments.

 
KLF2 was absent in anti-CD3/CD28-induced activated T cells but was expressed in cells treated with D4 DA receptor agonist

We next investigated whether activation of the D4 class of DA receptors was associated with the expression of KLF2, the transcription factor that regulates quiescence in T cells (16). Unstimulated T cells showed considerable expression of KLF2. In contrast, when these cells were stimulated with anti-CD3/CD28 Abs, the KLF2 expression was undetectable (Fig. 3, a and b) after 24 h of stimulation as previously reported (23). Furthermore when these cells were costimulated with the specific D4 DA receptor agonist PD 168,077 and with anti-CD3/CD28, the expression of KLF2 remained intact as shown by RT-PCR and Western blot analyses (Fig. 3, c and d). However, the D4 DA receptor agonist PD 168,077 alone, without any further stimulation of a TCR, had no effect on KLF2 expression (Fig. 3, c and d).


Figure 3
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  		FIGURE 3. Association of D4 DA receptor stimulation with the expression of KLF2, a transcription factor regulating T cell quiescence. a and b, Time kinetics of KLF2 expression in anti-CD3/CD28-induced stimulation of T cells; KLF2 expression was undetectable by both RT-PCR and Western blot analysis at 24 h after anti-CD3/CD28-induced stimulation. c and d, KLF2 remained expressed in D4 agonist-treated cells even after 24 h of stimulation. RT-PCR and Western blot analysis revealed robust expression of KLF2 in unstimulated T cells. KLF2 was absent in anti-CD3/CD28-stimulated cells at 24 h but present in D4 agonist-treated cells even at 24 h after stimulation. D4 agonist treatment of unstimulated cells had no effect on KLF2 expression. e, Down-regulation of ERK1/ERK2 phosphorylation by D4 agonist treatment. When T cells were stimulated with anti-CD3/CD28, ERK1/ERK2 was significantly phosphorylated. In contrast, when cells were treated with the D4 receptor agonist PD 168,077, ERK1/ERK2 failed to phosphorylate in response to CD3/CD28-induced stimulation, which was correlated with the expression of KLF2. D4 agonist treatment of unstimulated T cells had no effect on ERK1/ERK2 phosphorylation. f, KLF2 expression is specifically associated with down-regulation of ERK1/ERK2. When unstimulated T cells were pretreated with a MEK-1/MEK-2 inhibitor (U0126, a specific MEK inhibitor that inhibits the ERK1/2 signaling pathway) followed by stimulation with anti-CD3/CD28, KLF2 remained expressed after 24 h. Cells pretreated with either the p38 MAPK inhibitor SB203580 or the JNK inhibitor SP600125, followed by stimulation with anti-CD3/CD28, did not express KLF2, like cells stimulated with anti-CD3/CD28 alone. Results are representative of three separate experiments.

 
Inhibition of ERK1/ERK2 by the stimulation of D4 DA receptors is associated with the expression of KLF2 in T cells

Because the stimulation of ERK1/ERK2 is a critical signaling step for cell activation (24), we investigated the expression of ERK1/ERK2 following the activation of D4 DA receptors by PD 168,077 and its correlation with KLF2 expression in T cells. We observed that T cell activation by anti-CD3/CD28 was associated with the phosphorylation of ERK1/ERK2 (Fig. 3e). However, when these cells were treated with the specific D4 receptor agonist PD 168,077 in presence of anti-CD3/CD28 Abs, there was significant inhibition of ERK1/ERK2 phosphorylation (Fig. 3e), but KLF2 was strongly expressed in these cells (Fig 3, c and d). In contrast, the D4 DA receptor agonist PD 168,077 (1 µM) had no effect on ERK1/ERK2 phosphorylation in T cells not stimulated by anti-CD3/CD28 (Fig. 3e). Similarly, when these cells were pretreated with a MEK1/2 inhibitor (U0126), KLF2 remained expressed in them even after treatment with anti-CD3/CD28 (Fig. 3f), thereby indicating the involvement of the ERK1/ERK2 pathway in D4 DA receptor-mediated regulation of KLF2 expression in T cells. In contrast, the inhibition of p38MAPK by its specific inhibitor (SB203580) (Fig. 3f) or that of JNK activity (Fig. 3f) by its specific inhibitor (SP600125) failed to show similar effects on KLF2 expression.

The above experiments were also repeated with another specific D4 DA receptor agonist, ABT724 trihydrochloride, and similar results were observed (data not shown).

Stimulation of the D1/D5, D2, and D3 classes of DA receptors by specific agonists inhibit anti-CD3/CD28-induced T cell proliferation but do not show any effect on KLF2 expression

The dose responses (1 nM to 1 mM) of DA receptor agonists (D1/D5, D2, and D3) in inhibiting anti-CD3/CD28-induced T cell proliferation were investigated. It was observed that although the specified doses of the D1/D5 agonist SKF38393 (1 µM), the D2 agonist quinpirole (2 µM), and the D3 agonist, PD 128907 (5 µM) significantly inhibited anti-CD3/CD28-induced T cell proliferation with negligible cell death (data not shown), these doses did not induce KLF2 expression in anti-CD3/CD28-stimulated T cells (Fig. 4). Also, the inhibitory mechanisms of these DA receptors were different from those of the D4 DA receptors (7, 8). The present results therefore indicate that the induction of KLF2 in T cells is specific for the D4 class of DA receptors expressed in T cells.


Figure 4
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  		FIGURE 4. Stimulation of D1/D5, D2, and D3 receptor agonists did not show any effect on KLF2 expression in T cells activated with anti-CD3/CD28. Cells (1 x 106) were treated with 1 µM SKF 38393 (D1/D5 agonist), 2 µM quinpirole (Quin; D2 agonist), or 500 nM PD 128907 (D3 agonist) along with anti-CD3/CD28 stimulation. Results are representative of six separate experiments.

 
Taken together, our results indicate for the first time that stimulation of the D4 class of DA receptors in T cells is associated with its quiescent by expressing KLF2 via the ERK1/ERK2 pathway. Because quiescent plays a critical role in T cell survival (15, 16) and KLF2 is a dominant factor in regulating the quiescence state of the T cells (15, 16, 17, 18, 25, 26, 27), the present results demonstrate that the correlation between D4 DA receptor activation and the expression of KLF2 in human T cells may be one of the regulatory mechanisms of neurotransmitter-mediated T cell homeostasis. Thus, investigating the molecular switches that regulate lymphocyte quiescence will enable us to gain a better understanding of cell cycle control in T lymphocytes. In addition, strategies for inducing quiescence by using specific D4 DA receptor agonists might be useful in the treatment of diseases in which uncontrolled T cell proliferation plays an important pathogenic role (15).


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by Defense Research and Development Organization, Government of India Grant LSRB-24/EPB (to P.S.D.) and National Institutes of Health Grant CA118265 (to S.B.). Back

2 C.S., S.D., and D.C. equally contributed to this work. Back

3 Address correspondence and reprint requests to Dr. Partha Sarathi Dasgupta, Signal Transduction and Biogenic Amines Laboratory, 37 S.P. Mukherjee Road, Kolkata 700026, India. E-mail address: partha42002{at}yahoo.com or Dr. Sujit Basu, Mayo Clinic Cancer Center and Department of Biochemistry and Molecular Biology, 200 First Street Southwest, Guggenheim 1494, Mayo Clinic, Rochester, MN 55905. E-mail address: basu.sujit{at}mayo.edu Back

4 Abbreviations used in this paper: DA, dopamine; KLF, Krüppel-like factor; 7-AAD, 7-aminoactinomycin D. Back

Received for publication July 20, 2006. Accepted for publication October 3, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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