title: Dopamine Receptor D3 Signaling on CD4+ T Cells Favors Th1- and Th17-Mediated Immunity.
abstract: Dopamine receptor D3 (DRD3) expressed on CD4(+) T cells is required to promote neuroinflammation in a murine model of Parkinson's disease. However, how DRD3 signaling affects T cell-mediated immunity remains unknown. In this study, we report that TCR stimulation on mouse CD4(+) T cells induces DRD3 expression, regardless of the lineage specification. Importantly, functional analyses performed in vivo using adoptive transfer of OVA-specific OT-II cells into wild-type recipients show that DRD3 deficiency in CD4(+) T cells results in attenuated differentiation of naive CD4(+) T cells toward the Th1 phenotype, exacerbated generation of Th2 cells, and unaltered Th17 differentiation. The reciprocal regulatory effect of DRD3 signaling in CD4(+) T cells favoring Th1 generation and impairing the acquisition of Th2 phenotype was also reproduced using in vitro approaches. Mechanistic analysis indicates that DRD3 signaling evokes suppressor of cytokine signaling 5 expression, a negative regulator of Th2 development, which indirectly favors acquisition of Th1 phenotype. Accordingly, DRD3 deficiency results in exacerbated eosinophil infiltration into the airways of mice undergoing house dust mite-induced allergic response. Interestingly, our results show that, upon chronic inflammatory colitis induced by transfer of naive CD4(+) T cells into lymphopenic recipients, DRD3 deficiency not only affects Th1 response, but also the frequency of Th17 cells, suggesting that DRD3 signaling also contributes to Th17 expansion under chronic inflammatory conditions. In conclusion, our findings indicate that DRD3-mediated signaling in CD4(+) T cells plays a crucial role in the balance of effector lineages, favoring the inflammatory potential of CD4(+) T cells.
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago 8370146, Chile;
authors.forename: Francisco
authors.initials: F
authors.lastname: Contreras
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile;
authors.forename: Carolina
authors.initials: C
authors.lastname: Prado
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile;
authors.forename: Hugo
authors.initials: H
authors.lastname: González
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile;
authors.forename: Dafne
authors.initials: D
authors.lastname: Franz
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile;
authors.forename: Francisco
authors.identifier: 0000-0002-6853-7846
authors.initials: F
authors.lastname: Osorio-Barrios
authors.affiliation: Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; and.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Osorio
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile;
authors.forename: Valentina
authors.initials: V
authors.lastname: Ugalde
authors.affiliation: Laboratorio de Inmunoterapia Génica, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Lopez
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago 8370146, Chile;
authors.forename: Daniela
authors.initials: D
authors.lastname: Elgueta
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile;
authors.forename: Alicia
authors.initials: A
authors.lastname: Figueroa
authors.affiliation: Laboratorio de Inmunoterapia Génica, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Lladser
authors.affiliation: Laboratorio de Neuroinmunología, Fundación Ciencia y Vida, Ñuñoa 7780272, Santiago, Chile; Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas, Universidad Andrés Bello, Santiago 8370146, Chile; rpacheco@cienciavida.org.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Pacheco
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020078:Neurogenic Inflammation / Q000276:immunology*; D010300:Parkinson Disease / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology*; D058408:Th1-Th2 Balance; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D011948:Receptors, Antigen, T-Cell; D050637:Receptors, Dopamine D3; C485811:Socs5 protein, mouse; D050826:Suppressor of Cytokine Signaling Proteins