Dopamine receptor D2 on CD4(+) T cells is protective against neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4(+) T cells has been involved in PD pathophysiology. Human and murine lymphocytes express all the five subtypes of dopamine receptors (DRs), DRD1 to DRD5. However, roles of DRs particularly DRD2 expressed on CD4(+) T cells in PD remain elucidated. Global Drd1- or Drd2-knockout (Drd1(-/-) or Drd2(-/-)) mice or CD4(+) T cell-specific Drd2-knockout (Drd2(fl/fl)/CD4(Cre)) mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD with the different mutants. On the 7th day following MPTP injection, mice were assessed for dopaminergic neurodegeneration, locomotor impairments, microglial activation, as well as CD4(+) T-cell differentiation and function. Furthermore, in vitro CD4(+) T cells were exposed to DRD2 agonist and antagonist and then differentiation and function of the cells were determined. MPTP induced dopaminergic neuronal loss in the nigrostriatal system, motor coordinative and behavioral impairments, microglial activation, and CD4(+) T-cell polarization to pro-inflammatory T-helper (Th)1 and Th17 phenotypes. Importantly, either Drd2(-/-) or Drd2(fl/fl)/CD4(Cre) mice manifested more severe dopaminergic neurodegeneration, motor deficits, microglial activation, and CD4(+) T-cell bias towards Th1 and Th17 phenotypes in response to MPTP, but Drd1(-/-) did not further alter MPTP intoxication. DRD2 agonist sumanirole inhibited shift of CD4(+) T cells obtained from MPTP-intoxicated mice to Th1 and Th17 phenotypes and DRD2 antagonist L-741,626 reversed sumanirole effects. These findings suggest that DRD2 expressed on CD4(+) T cells is protective against neuroinflammation and neurodegeneration in PD. Thus, developing a therapeutic strategy of stimulating DRD2 may be promising for mitigation of PD.