Dopamine released by dendritic cells polarizes Th2 differentiation

Abstract

A major neurotransmitter dopamine transmits signals via five different seven transmembrane G protein-coupled receptors termed D1-D5. It is now evident that dopamine is released from leukocytes and acts as autocrine or paracrine immune modulator. However, the role of dopamine for dendritic cells (DCs) and T(h) differentiation remains unclear. We herein demonstrate that human monocyte-derived dendritic cells (Mo-DCs) stored dopamine in the secretary vesicles. The storage of dopamine in Mo-DCs was enhanced by forskolin and dopamine D2-like receptor antagonists via increasing cyclic adenosine 3',5'-monophosphate (cAMP) formation. Antigen-specific interaction with naive CD4(+) T cells induced releasing dopamine-including vesicles from Mo-DCs. In naive CD4(+) T cells, dopamine dose dependently increased cAMP levels via D1-like receptors and shifts T-cell differentiation to T(h)2, in response to anti-CD3 plus anti-CD28 mAb. Furthermore, we demonstrated that dopamine D2-like receptor antagonists, such as sulpiride and nemonapride, induced a significant DC-mediated T(h)2 differentiation, using mixed lymphocyte reaction between human Mo-DCs and allogeneic naive CD4(+) T cells. When dopamine release from Mo-DCs is inhibited by colchicines (a microtubule depolymerizer), T-cell differentiation shifts toward T(h)1. These findings identify DCs as a new source of dopamine, which functions as a T(h)2-polarizing factor in DC-naive T-cell interface.

Stimulation of Dopamine Receptor D5 Expressed on Dendritic Cells Potentiates Th17-Mediated Immunity

“…2) suggest an autocrine mechanism of action of this neurotransmitter. These results are in agreement with previous observations that an anti-DA Ab produced positive immunoreactivity in human monocyte-derived DCs (25). Notably, only D5R expression decreased upon LPS-induced DC maturation, suggesting a role for this receptor during DC maturation.…”

“…In Tregs, endogenous DA signals through D1R/D5R in a paracrine/autocrine manner resulting in the downregulation of Treg function (23). In DCs, recent pharmacological evidence suggests that the antagonism of D1R/D5R expressed on DCs could impair the polarization of naive CD4 + T cells toward the Th17 phenotype (24,25). However, as the D1R/D5R antagonist used in these studies is also an agonist for serotonin receptors (26,27) and serotonin receptors are also expressed on DCs (28), the individual contributions of specific DARs and serotonin receptors in this phenomenon are not clear (24).…”

“…5C, 5D). Because DA has also been involved in the polarization of CD4 + T cells toward Th2 phenotype (25), we evaluated the presence of IL-4 + cells in the population of CD4 + T cells infiltrating the CNS. We did not detect IL-4-producing cells in the CNS of mice receiving WT or D5RKO DCs (data not shown), thereby discarding the participation of Th2 cells.…”

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

“…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).…”

“…Pharmacological evidence obtained from a group of studies performed with human T cells has suggested that among five DARs described so far (D1R-D5R), both type I (D1R and D5R) and type II (D2R, D3R, and D4R) contribute to the regulation of T cell function. In this regard, Nakano et al (27) have suggested that stimulation of type I DARs expressed on human naive CD4 + T cells would contribute to production of Th2 cytokines, whereas Cosentino et al (32) have suggested that stimulation of type I DARs on Tregs would decrease IL-10 and TGF-b production. Sarkar et al (25) have described that D4R stimulation on human T cells promotes quiescence.…”