Antagonizing dopamine D1-like receptor inhibits Th17 cell differentiation: Preventive and therapeutic effects on experimental autoimmune encephalomyelitis Kazuhisa Nakano a,b , Takehiro Higashi a , Kumiko Hashimoto a , Rie Takagi a , Yoshiya Tanaka b , Sho Matsushita a, * a The Department of Allergy and Immunology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 350-0495, Japan b The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan article info Article history: Received 5 June 2008 Available online 17 June 2008 Keywords: Dopamine receptor Dendritic cell Experimental autoimmune encephalomyelitis Th17 D1-like-R antagonist D2-like-R antagonist abstract Five types of dopamine receptors, termed D1 to D5, have been identified to date. The D1 and D5 receptors form the D1-like group that couples with the Gas class of G proteins, while D2, D3 and D4 form the D2- like group that couples with the Gai class of G proteins. A D2-like-receptor (D2-like-R) antagonist L750667 induced dendritic cell (DC)-mediated Th17 differentiation. In contrast, a D1-like-R antagonist SCH23390 inhibited DC-mediated Th17 differentiation. The D1-like-Rs were expressed on both DCs and T cells, whereas D2-like-Rs were marginally expressed on CD4 + CD45RA + naïve T cells. In addition, SCH23390 had the ability to prevent experimental autoimmune encephalomyelitis (EAE) in mice. Spleen cells from EAE mice showed decreased IL-17 production, when SCH23390 was administered. Adoptive transfer of DCs treated with SCH23390 successfully prevented EAE. These findings indicate that antago- nizing D1-like-Rs on DCs inhibits Th17 differentiation, thereby leading to an amelioration of EAE. Ó 2008 Elsevier Inc. All rights reserved. Dendritic cells (DCs) are antigen-presenting cells specialized to activate naïve T lymphocytes and initiate primary immune responses. The different classes of specific immune responses are driven by the biased development of antigen-specific effector CD4 + T-cell subsets such as Th1, Th2 and Th17 cells, that activate different components of cellular and humoral immunity. The Th17 lineage characteristically produces high levels of IL-17, and it has also been identified to represent a significant revision of the Th1–Th2 paradigm [1,2]. Moreover, Th17 cells have been re- ported to play not only critical roles in the immune responses to extracellular bacteria but also a pathogenetic role in autoimmunity [1,3–5]. DCs reside in an immature state in many nonlymphoid tis- sues such as the skin or airway mucosa which undergo frequent exposure to allergens, pathogens and chemicals. The stimulatory signal results from the ligation of TCRs by antigenic peptides presented by MHC class II molecules on the cell surface of DCs. TCR ligation with co-stimulation allows naïve T cells to de- velop into effector cells, normally accompanied by a high-level expression of selective sets of cytokines. It is well known that the balance of these cytokines and the resulting class of immune responses strongly depend on the conditions under which the DCs are primed. The ligands for many isoforms of toll-like receptors (TLRs), including certain nucleic acids, LPS and fungus-derived glycopro- tein molecules, alter the DC function, and induce Th1 differentia- tion in an antigen non-specific manner [6]. In this process, IL-12 produced by DCs is clearly correlates with the sensitization of Th1 [7]. On the other hand, DCs matured in the presence of PGE 2 or forskolin induce the differentiation of naïve CD4 + T cells toward Th2 via a cAMP cascade [8]. However, the specific molecules which positively induce a significant Th2 differentiation during the inter- action between DC and naïve CD4 + T cells still remains to be clar- ified, and the contribution of the DC itself to Th2 or Th17 differentiation remains unclear. In the present study, we show that dopamine D2-like-receptor (D2-like-R) antagonists, which are known as neuroleptics, have the ability to induce a significant DC-mediated Th17 differentia- tion, in a mixed lymphocyte reaction (MLR) between human monocyte-derived DCs and allogeneic naïve CD4 + T cells. Antago- nizing dopamine-receptor subtypes differentially affects Th17 polarization in vitro. D2-like antagonists judged to be Th17 adju- vants in vitro cause a marked deterioration of experimental auto- immune encephalomyelitis (EAE), whereas D1-like-R antagonists exhibit a marked improvement of EAE. 0006-291X/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.bbrc.2008.06.012 * Corresponding author. Fax: +81 49 294 2274. E-mail address: shomat@saitama-med.ac.jp (S. Matsushita). Biochemical and Biophysical Research Communications 373 (2008) 286–291 Contents lists available at ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc