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Dopamine Selectively Induces Migration and Homing of Naive CD8⁺ T Cells via Dopamine Receptor D3¹

Yoshiko Watanabe^*,, Takashi Nakayama^*, Daisuke Nagakubo^*, Kunio Hieshima^*, Zhe Jin^*, Fuminori Katou, Kenji Hashimoto and Osamu Yoshie^2,*

^* Department of Microbiology, Kinki University School of Medicine, Osaka-Sayama, Osaka, Japan; and Department of Oral and Maxillofacial Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

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 Gi 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.

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