Dopamine receptors D3 and D5 regulate CD4 +T-cell activation and differentiation by modulating ERK activation and cAMP production

•Adenylyl cyclase inhibition by dopamine receptor D3 favours CD4+ T-cell activation.•Dopamine receptor D5 signalling increases ERK activity reinforcing T-cell activation.•Late ERK2 inhibition exerted by dopamine receptor D3 enhances Th1-differentiation.

Dopamine receptors have been described in T-cells, however their signalling pathways coupled remain unknown. Since cAMP and ERKs play key roles regulating T-cell physiology, we aim to determine whether cAMP and ERK1/2-phosphorylation are modulated by dopamine receptor 3 (D3R) and D5R, and how this modulation affects CD4+ T-cell activation and differentiation. Our pharmacologic and genetic evidence shows that D3R-stimulation reduced cAMP levels and ERK2-phosphorylation, consequently increasing CD4+ T-cell activation and Th1-differentiation, respectively. Moreover, D5R expression reinforced TCR-triggered ERK1/2-phosphorylation and T-cell activation. In conclusion, these findings demonstrate how D3R and D5R modulate key signalling pathways affecting CD4+ T-cell activation and Th1-differentiation.