Dopaminergic regulation of immune cells via D ₃ dopamine receptor: a pathway mediated by activated T cells

Abstract

Neuro-immune interactions enable mutual regulation of the nervous and immune systems. To date, evidence exists for manipulations of immune cells by neurotransmitters in the periphery. In this study, we suggest the existence of a pathway by which the brain affects immune cells. The pathway we describe here is mediated by dopamine receptors expressed on activated T cells, termed blasts. Blasts can cross the blood brain barrier regardless of antigen specificity and can therefore encounter neurotransmitters in the brain. We show that blasts have a unique response to dopaminergic activation, which has no counterpart in resting T cells. Dopaminergic activation of blasts induces a Th1 bias in their cytokine profile and causes changes in surface marker expression. We further suggest that these changes can subsequently be transferred to peripheral T cells. We have tested this pathway in two in vivo systems: in rats exogenously administered with L-dopa, and in schizophrenia, which is characterized by a central nervous system-restricted increase in dopamine. In both models, peripheral T cells exhibit similar features to those of dopaminergically activated blasts. The existence of such a pathway by which the brain can regulate immune cells opens a conceptually new direction in neuro-immune interactions.

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

“…However, most of those studies have shown a number of DA-mediated inhibitory effects using high concentrations (.1 mM) that affect multiple DARs. In contrast, a study addressing the role of selective stimulation of D3R in human T cells have shown that pharmacologic stimulation of D3R in activated CD4 + T cells favors expression of the cell surface activation marker CD25 as well as production of the proinflammatory cytokine IFN-g (33). In agreement with this latter study, our findings in this study show both genetic and pharmacologic evidences indicating that D3R stimulation on CD4 + T cells favors T cell activation and production of the proinflammatory cytokines IFN-g and TNF-a (Fig.…”

“…It has also been described that stimulation of D3R in resting T cells favors activation of b 1 integrins and adhesion to fibronectin, two critical events required for cell migration (26,29). Importantly, Ilani et al (33) have suggested that D3R stimulation in human activated CD4 + T cells decrease IL-4 and IL-10 synthesis and potentiates IFN-g production, the hallmark cytokine of Th1 cells. The same authors have shown that pharmacologic D3R stimulation in human T cells potentiate expression of surface activation markers (33).…”

“…Importantly, Ilani et al (33) have suggested that D3R stimulation in human activated CD4 + T cells decrease IL-4 and IL-10 synthesis and potentiates IFN-g production, the hallmark cytokine of Th1 cells. 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.…”

“…Interestingly, expression of D3R is significantly reduced on circulating lymphocytes obtained from PD patients, and this reduction correlates with disease severity (34), thus suggesting a role for D3R expression on lymphocytes in PD physiopathology. Moreover, pharmacologic evidence has shown that stimulation of D3R expressed on human CD4 + T cells promotes enhanced production of IFN-g and TNF-a, both of which play critical roles stimulating and maintaining glial cell activation in PD (22,33,35).…”

“…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.…”