Dopamine receptors D3 and D5 regulate CD4+T-cell activation and differentiation by modulating ERK activation and cAMP production

Franz, Dafne; Contreras, Francisco; González, Hugo; Prado, Carolina; Elgueta, Daniela; Figueroa, Claudio; Pacheco, Rodrigo

doi:10.1016/j.jneuroim.2015.05.003

Cited by 43 publications

(52 citation statements)

References 56 publications

(104 reference statements)

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“…We have previously shown that activated Drd3 2/2 CD4 + T cells exhibit a slight impairment in IL-2 secretion compared with their WT counterparts (7,19). Accordingly, we next tested how DRD3 expression affects CD4 + T cell proliferation.…”

Section: Drd3 Expression On Cd4 + T Cells Does Not Alter Activation Bmentioning

confidence: 99%

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

Contreras

Prado

González

et al. 2016

The Journal of Immunology

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Dopamine receptor D3 (DRD3) expressed on CD4+ T cells is required to promote neuroinflammation in a murine model of Parkinson’s disease. However, how DRD3 signaling affects T cell–mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4+ T cells induces DRD3 expression, regardless of the lineage specification. Importantly, functional analyses performed in vivo using adoptive transfer of OVA-specific OT-II cells into wild-type recipients show that DRD3 deficiency in CD4+ T cells results in attenuated differentiation of naive CD4+ T cells toward the Th1 phenotype, exacerbated generation of Th2 cells, and unaltered Th17 differentiation. The reciprocal regulatory effect of DRD3 signaling in CD4+ T cells favoring Th1 generation and impairing the acquisition of Th2 phenotype was also reproduced using in vitro approaches. Mechanistic analysis indicates that DRD3 signaling evokes suppressor of cytokine signaling 5 expression, a negative regulator of Th2 development, which indirectly favors acquisition of Th1 phenotype. Accordingly, DRD3 deficiency results in exacerbated eosinophil infiltration into the airways of mice undergoing house dust mite–induced allergic response. Interestingly, our results show that, upon chronic inflammatory colitis induced by transfer of naive CD4+ T cells into lymphopenic recipients, DRD3 deficiency not only affects Th1 response, but also the frequency of Th17 cells, suggesting that DRD3 signaling also contributes to Th17 expansion under chronic inflammatory conditions. In conclusion, our findings indicate that DRD3-mediated signaling in CD4+ T cells plays a crucial role in the balance of effector lineages, favoring the inflammatory potential of CD4+ T cells.

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Section: Drd3 Expression On Cd4 + T Cells Does Not Alter Activation Bmentioning

confidence: 99%

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

Contreras

Prado

González

et al. 2016

The Journal of Immunology

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“…As for T cells, the focus of the current study: dopamine itself at low physiological concentrations of ~10 −8 –10 −7 M (10–100 nM), as well as selective D2R, D3R and D4R agonists at ~10 −8 –10 −6 M, usually activate on their own resting normal human T cells, and induce multiple potent and beneficial T‐cell effects. The dopamine‐induced beneficial effects on resting T cells include, but not limited to: T cell adhesion to glycoproteins of the extracellular matrix, chemotactic migration, homing, cytokine secretion, activation of downstream signaling, increased expression on key receptors on the cell surface, and various other effects (reviewed, for example, in refs ).…”

Section: Introductionmentioning

confidence: 99%

“…We chose to focus in this study on the D1‐like receptors in T cells, as previous studies have shown that the binding of these receptors in some activated immune cells by selective D1‐like receptor analogues (i.e. the analogues being defined as either DR agonists or antagonists, based on their effects on other non‐immune cells, primarily neural cells) induces potent suppressive effects on these cells …”

Section: Introductionmentioning

confidence: 99%

Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1‐like receptor agonist: Fenoldopam

et al. 2019

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Activated T cells are pathological in various autoimmune and inflammatory diseases including Psoriasis, and also in graft rejection and graftversus-host-disease. In these pathological conditions, selective silencing of activated T cells through physiological receptors they express remains a clinical challenge. In our previous studies we found that activation of dopamine receptors (DRs) in resting human T cells activates these cells, and induces by itself many beneficial T cell functions. In this study, we found that normal human T cells express all types of DRs, and that expression of D1R, D4R and D5R increases profoundly after T cell receptor (TCR) activation. Interestingly, DR agonists shift the membrane potential (V m ) of both resting and activated human T cells, and induces instantaneous T cell depolarization within 15 seconds only. Thus, activation of DRs in T cells depolarize these immune cells, alike activation of DRs in neural cells. The skin of Psoriasis patients contains 20-fold more D1R + T cells than healthy human skin. In line with that, 25-fold more D1R + T cells are present in Psoriasis humanized mouse model. Highly selective D1-like receptor agonists, primarily Fenoldopam (Corlopam)a D1-like receptor agonist and a drug used in hypertension, induced the following suppressive effects on activated T cells of Psoriasis patients: reduced chemotactic migration towards the chemokine SDF-1/ CXCL12; reduced dramatically the secretion of eight cytokines: tumor necrosis factor-a, interferon-c, interleukin-1b (IL-1b), IL-2, IL-4, IL-6, IL-8 and IL-10; and reduced three T cell activation proteins/markers: CD69, CD28 and IL-2. Next, we invented a novel topical/dermal Fenoldopam formulation, allowing it to be spread on, and providing prolonged and regulated release in, diseased skin. Our novel topical/dermal Fenoldopam: reduced secretion of the eight cytokines by activated human T cells; reduced IL-1b and IL-6 secretion by human lipopolysaccharide-inflamed skin; eliminated preferentially >90% of live and large/proliferating human T cells. Together, our findings show for the first time that both resting and activated T cells are depolarized instantaneously via DRs, and that targeting D1-like receptors in activated T cells and inflamed human skin by Fenoldopam, in Psoriasis, and potentially in other T cell-mediated diseases, could be therapeutic. Validation in vivo is required.

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“…Isolated human lymphocytes were activated with IL-2 (80 ng/mL), anti-CD3e (50 ng/mL), and anti-CD28 (50 ng/mL) for 24 h (20). They were then transfected with miR-124 agomir (300 nM), LNA (200 ng/mL), or LNA together with nicotine (1 µM) separately (for detailed information, see the corresponding figure captions).…”

Section: Human Peripheral Blood Lymphocyte Activation and Transfectionmentioning

confidence: 99%

MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1

et al. 2020

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Dopamine receptors D3 and D5 regulate CD4+T-cell activation and differentiation by modulating ERK activation and cAMP production

Cited by 43 publications

References 56 publications

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity

Instantaneous depolarization of T cells via dopamine receptors, and inhibition of activated T cells of Psoriasis patients and inflamed human skin, by D1‐like receptor agonist: Fenoldopam

MicroRNA124-IL6R Mediates the Effect of Nicotine in Inflammatory Bowel Disease by Shifting Th1/Th2 Balance Toward Th1

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