Dopaminergic signalling through dopamine receptor D2 favours the functional stability of regulatory T cells mitigating gut inflammation and neuroinflammation
Year: 2026
Type: preprint
Abstract: Parkinson’s disease (PD) is characterised by progressive dopaminergic neurodegeneration, α-synuclein (αSyn) accumulation and chronic neuroinflammation. Regulatory T (Treg) cells restrain inflammatory responses in both the central nervous system and the intestine, but the mechanisms controlling their function during PD remain incompletely understood. Here, we investigated the role of dopamine receptor D2 (Drd2) signalling in T-cells, with particular emphasis on Treg differentiation, phenotypic stability and suppressive activity. Using an AAV-αSyn model of PD, we found that Drd2 deficiency in CD4⁺ T-cells exacerbated neuroinflammation, dopaminergic neuronal loss and motor impairment, whereas selective Drd2 deficiency in CD8⁺ T-cells did not reproduce this phenotype. Drd2 deficiency in CD4⁺ T-cells selectively increased T-cell infiltration into the SN, while reducing the frequency of splenic Treg cells without affecting Th1, Th17 or TNF-α-producing CD4⁺ T-cell subsets. In vitro, Drd2 -deficient naïve CD4⁺ T-cells displayed impaired differentiation into Foxp3⁺ Treg cells and reduced TGF-β production. Moreover, activated Drd2 -deficient Treg cells exhibited decreased Foxp3 expression and increased production of IL-17 and IFN-γ without altered viability. In a model of dextran sodium sulphate-induced colitis, adoptively transferred Drd2 -deficient Treg cells failed to attenuate body-weight loss and colon shortening. Although their recruitment to the colonic lamina propria was preserved, these cells showed reduced maintenance of Foxp3 expression. Collectively, these findings identify Drd2 signalling as a key regulator of Treg differentiation, phenotypic stability and suppressive function, thereby limiting intestinal inflammation and αSyn-associated dopaminergic neurodegeneration.
Source: Research Square
Institutions: Universidad San Sebastián, Fundación Ciencia and Vida
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7224783567