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

Abstract

The nervous systems affect immune functions by releasing neurohormones and neurotransmitters. A neurotransmitter dopamine signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. The secondary lymphoid tissues are highly innervated by sympathetic nerve fibers that store dopamine at high contents. Lymphocytes also produce dopamine. In this study, we examined expression and function of dopamine receptors in lymphocytes. We found that D3 was the predominant subtype of dopamine receptors in the secondary lymphoid tissues and selectively expressed by naive CD8+ T cells of both humans and mice. Dopamine induced calcium flux and chemotaxis in mouse L1.2 cells stably expressing human D3. These responses were almost completely inhibited by pertussis toxin, indicating that D3 was coupled with the Gαi class of G proteins. Consistently, dopamine selectively induced chemotactic responses in naive CD8+ T cells of both humans and mice in a manner sensitive to pertussis toxin and D3 antagonists. Dopamine was highly synergistic with CCL19, CCL21, and CXCL12 in induction of chemotaxis in naive CD8+ T cells. Dopamine selectively induced adhesion of naive CD8+ T cells to fibronectin and ICAM-1 through activation of integrins. Intraperitoneal injection of mice with dopamine selectively attracted naive CD8+ T cells into the peritoneal cavity. Treatment of mice with a D3 antagonist U-99194A selectively reduced homing of naive CD8+ T cells into lymph nodes. Collectively, naive CD8+ T cells selectively express D3 in both humans and mice, and dopamine plays a significant role in migration and homing of naive CD8+ T cells via D3.

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

“…Expression of DARs in T cells, including D3R, is very dynamic and depends on the activation state, specific T cell subset, pathologic conditions, and treatments (15,20,22,26,28,29,(40)(41)(42)(43)(44). In this regard and interestingly, a decreased D3R expression in PBLs obtained from PD patients has been observed, which correlates with the degree of disease severity (34).…”

“…Considering that RAG1KO mice lack T and B cells but they have normal monocytes, macrophages, DCs, and other leukocyte populations present in splenocytes, D3R expressed in B cells and/or CD8 + T cells could be responsible for the additional contribution to MPTP-induced neurodegeneration observed in RAG1KO mice transferred with WT splenocytes when compared with those RAG1KO mice transferred with WT CD4 + T cells. In this regard, D3R expression has been described in CD8 + T cells as well as in B cells (20,26). Importantly, only CD8 + T cells but not B cells have been found infiltrated into the SN of PD in human patients and mice treated with MPTP (6,50).…”

“…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 contrast, Besser et al (22) have shown evidence suggesting that stimulation of D2R and D3R in human resting T cells obtained from healthy donors would favor production of IL-10 and TNF-a, respectively. 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.…”

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

“…EAE is mediated mainly by T cells, but B cells also contribute to the initiation and development of the disease (43,45,46). Type I DARs as well as serotonin receptors have been found to be expressed on many types of immune cells including DCs (47), T cells (23,48,49), and B cells (50,51). Therefore, systemic treatment with SCH could affect several types of immune cells.…”