Physiological Concentrations of Dopamine Inhibit the Proliferation and Cytotoxicity of Human CD4+ and CD8+ T Cells in vitro: A Receptor-Mediated Mechanism

Saha, Bodhisattwa; Mondal, Amal Chandra; Majumder, Jahar; Basu, Sujit; Dasgupta, Partha

doi:10.1159/000049004

Cited by 101 publications

(99 citation statements)

References 25 publications

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“…Previous studies showing that pharmacological stimulation of DRD3 modulates cytokine production by human T cells in vitro (13,14,25), together with the results presented above, prompted us to investigate whether DRD3 expression contributes to CD4 + T cell differentiation into effector phenotypes. Whereas Drd3 2/2 CD4 + T cells induced IL-17A expression similarly to their WT counterparts under Th17-skewing conditions, they showed a significantly lower frequency of IFN-g-producing cells when exposed to Th1-polarizing signals (Fig.…”

Section: Th1 But Not Th17 Differentiation Is Favored By Drd3 Expresmentioning

confidence: 97%

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: Th1 But Not Th17 Differentiation Is Favored By Drd3 Expresmentioning

confidence: 97%

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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“…The same authors have shown that pharmacologic D3R stimulation in human T cells potentiate expression of surface activation markers (33). In contrast, Saha et al (23,24) have shown that DA, at concentrations that should selectively stimulate D3R, inhibits human T cell proliferation.…”

Section: P Arkinson's Disease (Pd) Is a Neurodegenerative Disordermentioning

confidence: 97%

“…Regarding expression of DA receptors (DARs) in immune cells, these receptors have been found not only in cells of the innate immune response such as dendritic cells (DCs), NK cells, macrophages/monocytes and granulocytes (19)(20)(21) but also in cells of the adaptive immune response such as B cells, CD8 + T cells, and CD4 + T cells (22)(23)(24)(25)(26)(27)(28)(29)(30). Despite being lesser studied than in human T cells, DARs expression has also been described in murine T cells (26,31).…”

Section: P Arkinson's Disease (Pd) Is a Neurodegenerative Disordermentioning

confidence: 99%

“…Pharmacological evidence has shown that D3R stimulation of human T cells in vitro may modulate both expression of T cell activation markers and production of effector cytokines (22)(23)(24)33). Accordingly, we next addressed the question of whether D3R expressed on CD4 + T cells affects T cell activation and differentiation.…”

Section: D3r Expressed On Cd4 + T Cells Favors T Cell Activation and mentioning

confidence: 99%

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Dopamine Receptor D3 Expressed on CD4+ T Cells Favors Neurodegeneration of Dopaminergic Neurons during Parkinson’s Disease

González

Contreras

Prado

et al. 2013

The Journal of Immunology

127

145

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Emerging evidence has demonstrated that CD4+ T cells infiltrate into the substantia nigra (SN) in Parkinson's disease (PD) patients and in animal models of PD. SN-infiltrated CD4+ T cells bearing inflammatory phenotypes promote microglial activation and strongly contribute to neurodegeneration of dopaminergic neurons. Importantly, altered expression of dopamine receptor D3 (D3R) in PBLs from PD patients has been correlated with disease severity. Moreover, pharmacological evidence has suggested that D3R is involved in IFN-γ production by human CD4+ T cells. In this study, we examined the role of D3R expressed on CD4+ T cells in neurodegeneration of dopaminergic neurons in the SN using a mouse model of PD. Our results show that D3R-deficient mice are strongly protected against loss of dopaminergic neurons and microglial activation during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD. Notably, D3R-deficient mice become susceptible to MPTP-induced neurodegeneration and microglial activation upon transfer of wild-type (WT) CD4+ T cells. Furthermore, RAG1 knockout mice, which are devoid of T cells and are resistant to MPTP-induced neurodegeneration, become susceptible to MPTP-induced loss of dopaminergic neurons when reconstituted with WT CD4+ T cells but not when transferred with D3R-deficient CD4+ T cells. In agreement, experiments analyzing activation and differentiation of CD4+ T cells revealed that D3R favors both T cell activation and acquisition of the Th1 inflammatory phenotype. These findings indicate that D3R expressed on CD4+ T cells plays a fundamental role in the physiopathology of MPTP-induced PD in a mouse model.

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“…Dopamine also is an agonist of α-and β-adrenergic receptors, but exerts its effects mainly via specific dopaminergic receptors that can be found on a large number of cells including lymphocytes (83). In physiological concentrations, dopamine inhibits the proliferation and cytotoxicity of human CD4 + and CD8 + lymphocytes in vivo and in vitro via the dopamine receptors (52,(84)(85)(86), paralleling the adverse effects of epinephrine and norepinephrine. Lately, the gut has also been identified as an alternate source of catecholamines during sepsis in rodents, releasing norepinephrine into the portal vein and thereby altering the functional state of hepatocytes and Kupffer cells, unexpectedly contributing to hepatocellular dysfunction during sepsis (87)(88)(89)(90).…”

Section: Foolishly Unlocking Pandora's Box?mentioning

confidence: 99%

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

Flierl

Rittirsch

Huber‐Lang

et al. 2008

Mol Med

165

114

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It is well established that catecholamines (CAs), which regulate immune and inflammatory responses, derive from the adrenal medulla and from presynaptic neurons. Recent studies reveal that T cells also can synthesize and release catecholamines which then can regulate T cell function. We have shown recently that macrophages and neutrophils, when stimulated, can generate and release catecholamines de novo which, then, in an autocrine/paracrine manner, regulate mediator release from these phagocytes via engagement of adrenergic receptors. Moreover, regulation of catecholamine-generating enzymes as well as degrading enzymes clearly alter the inflammatory response of phagocytes, such as the release of proinflammatory mediators. Accordingly, it appears that phagocytic cells and lymphocytes may represent a major, newly recognized source of catecholamines that regulate inflammatory responses.

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Physiological Concentrations of Dopamine Inhibit the Proliferation and Cytotoxicity of Human CD4+ and CD8+ T Cells in vitro: A Receptor-Mediated Mechanism

Cited by 101 publications

References 25 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

Dopamine Receptor D3 Expressed on CD4+ T Cells Favors Neurodegeneration of Dopaminergic Neurons during Parkinson’s Disease

Catecholamines—Crafty Weapons in the Inflammatory Arsenal of Immune/Inflammatory Cells or Opening Pandora’s Box?

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