Dopamine Receptor D3 Signaling on CD4(+) T Cells Favors Th1-and Th17-Mediated Immunity

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.This work was supported by Fondo Nacional de Desarrollo Cientı´fico y Tecnolo´gico de Chile Grant 1130271, Comisio´n Nacional de Investigacio´n Cientı´fica y Tecnolo´gica de Chile Grant PFB-16, and Michael J. Fox Foundation Grant 10332 (to R.P.), as well as by the Programa de Formacio´n de Capital Humano Avanzado–Magı´ster Nacional, Comisio´n Nacional de Investigacio´n Cientı´fica y Tecnolo´gica de Chile Grants 22140120 (to F.O.-B.) and 22150983 (to E.L.), the Programa Atraccio´n e Insercio´n de Capital Humano Avanzado, Comisio´n Nacional de Investigacio´n Cientı´fica y Tecnolo´gica de Chile Grant 82130031 (to F.O.), and a Universidad Andre´s Bello Ph.D. fellowship (to D.E.)