Abstract
Dopamine is a key neurotransmitter that induces critical effects in the nervous system and in many peripheral organs, via 5 dopamine receptors (DRs): D1R–D5R. Dopamine also induces many direct and very potent effects on many DR-expressing immune cells, primarily T cells and dendritic cells. In this review, we focus only on dopamine receptors, effects and production in T cells. Dopamine by itself (at an optimal concentration of~0.1 nM) induces multiple function of resting normal human T cells, among them: T cell adhesion, chemotactic migration, homing, cytokine secretion and others. Interestingly, dopamine activates resting effector T cells (Teffs), but suppresses regulatory T cells (Tregs), and both effects lead eventually to Teff activation. Dopamine-induced effects on T cells are dynamic, context-sensitive and determined by the: T cell activation state, T cell type, DR type, and dopamine concentration. Dopamine itself, and also few dopaminergic molecules/ drugs that are in clinical use for cardiac, neurological and other non-immune indications, have direct effects on human T cells (summarized in this review). These dopaminergic drugs include: dopamine = intropin, L-DOPA, bromocriptine, pramipexole, pergolide, haloperidol, pimozide, and amantadine. Other dopaminergic drugs were not yet tested for their direct effects on T cells. Extensive evidence in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) show dopaminergic dysregulations in T cells in these diseases: D1-like DRs are decreased in Teffs of MS patients, and dopamine does not affect these cells. In contrast, D1-like DRs are increased in Tregs of MS patients, possibly causing functional Treg impairment in MS. Treatment of MS patients with interferon β (IFN-β) increases D1-like DRs and decreases D2-like DRs in Teffs, decreases D1-like DRs in Tregs, and most important: restores responsiveness of patient’s Teffs to dopamine. DR agonists and antagonists confer some benefits in EAE-afflicted animals. In a single clinical trial, MS patients did not benefit from bromocriptine, which is a D2-like DR agonist. Nevertheless, multiple evidence showing dopaminergic abnormalities in T cells in MS encourages testing other DR analogues/drugs in MS, possibly as “add-on” to IFN-β or other MS-immunomodulating therapies. Together, abnormalities in DRs in T cells can contribute to MS, and DRs in T cells can be therapeutic targets in MS. Finally and in a more general scope: the direct effects of all dopaminergic drugs on human T cells should be studied in further depth, and also taken into consideration whenever treating patients with any disease, to avoid detrimental side effects on the immune system of the patients.
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Abbreviations
- L-DOPA:
-
3,4-Dihydroxyphenylalanine
- CAs:
-
Catecholamines
- DCs:
-
Dendritic cells
- DR:
-
Dopamine receptor
- EAE:
-
Experimental autoimmune encephalomyelitis
- MS:
-
Multiple sclerosis
- PBMCs:
-
Peripheral blood mononuclear cells
- PBLs:
-
Peripheral blood lymphocytes
- TH:
-
Tyrosine hydroxylase
- NK cells:
-
Natural killer cells
- PD:
-
Parkinson’s disease
- SLE:
-
Systemic lupus erythematosus
- Teff:
-
Effector T cell
- Treg:
-
Regulatory T cell
- CSF:
-
Cerebrospinal fluid
- RA:
-
Rheumatoid arthritis
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Levite, M., Marino, F. & Cosentino, M. Dopamine, T cells and multiple sclerosis (MS). J Neural Transm 124, 525–542 (2017). https://doi.org/10.1007/s00702-016-1640-4
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DOI: https://doi.org/10.1007/s00702-016-1640-4