Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates β1 integrin function

Abstract

Dopamine by itself has not up to now been reported to activate T cell function. We show here that dopamine interacts directly with dopaminergic receptors on normal human T cells and triggers β1 integrin‐mediated T cell adhesion to a major extracellular matrix component, fibronectin (FN). Such adhesion is a characteristic feature of activated T cells, and is critical for trafficking and extravasation of T cells across blood vessels and tissue barriers. Seven dopamine D2/D3 receptor agonists and antagonists were used to identify the receptor subtypes with which dopamine specifically interacts to activate T cells. The D3 dopamine receptor agonist, 7‐hydroxy‐DPAT (DPAT), mimics the effects of dopamine, and the effects of both dopamine and DPAT are blocked by a specific D3 receptor antagonist, U‐maleate. The dopamine receptor agonists bromocriptine and pergolide mimic the direct effect of dopamine on the β1 integrin function, while the dopamine receptor antagonists butaclamol and haloperidol suppress it, suggesting additional signaling via the dopamine D2 receptor subtype. Our study shows, for the first time, that dopamine can directly activate T cells via ist specific receptors and suggests a possible role for dopamine in integrin‐mediated cellular trafficking and extravasation of T cells in the central nervous system and possibly also in the periphery. Finally, we suggest that the reported changes in the D3 and D2 receptor RNA levels in peripheral blood lymphocytes of individuals with schizophrenia, Parkinson's disease, Alzheimer's disease and migraine can serve not only as a ‘passive’ diagnostic marker, but primarily reflect the dynamic functional dopamine‐T cell interactions in these diseases.

Dopamine Selectively Induces Migration and Homing of Naive CD8+ T Cells via Dopamine Receptor D3

“…5). Similarly, Levite et al (25) reported that the activation of ␤ 1 integrin by dopamine was bell shaped with the optimal concentrations in the range of 10 to 100 nM. Thus, the biphasic type of dose responses may be in part responsible for such dichotomous activities.…”

“…Furthermore, they also demonstrated that a D3-selective agonist 7-OH-DPAT (1) mimicked and a D3-selective antagonist U-99194A (29) blocked the observed effects of dopamine (25). We have extended their observations and shown that dopamine as well as a D3-selective agonist 7-OH-DPAT (1) selectively induce adhesion of human naive CD8 ϩ T cells to fibronectin via D3 through activation of VLA-4 and VLA-5 integrins (Fig.…”

“…anti-␣ 4 integrin and anti-␣ 5 integrin, but not control IgG, significantly inhibited dopamine-induced adhesion of CD45RA ϩ CD8 ϩ T cells to fibronectin (25). Thus, dopamine selectively induces adhesion of CD45RA ϩ naive CD8 ϩ T cells to fibronectin via D3 through activation of VLA-4 and VLA-5.…”

“…Previously, Levite et al (25) reported that dopamine induced adhesion of human T cells to fibronectin, a major extracellular matrix component, by triggering activation of the ␤ 1 integrins VLA-4 and VLA-5. Furthermore, they also demonstrated that a D3-selective agonist 7-OH-DPAT (1) mimicked and a D3-selective antagonist U-99194A (29) blocked the observed effects of dopamine (25).…”

“…Dopamine may also play a role in the microenvironmental localization of naive CD8 ϩ T cells within the secondary lymphoid tissues by triggering activation of ␤ 1 integrins (Fig. 6A) (25). Migration of lymphocytes into the secondary lymphoid tissues is now known to be controlled by the homeostatic chemokines SLC/CCL21 and ELC/CCL19 that are presented on high endothelial venules of the secondary lymphoid tissues (21,(37)(38)(39)(40)(41).…”