TNFR2 stimulation induces pathological T-cell activation in a Parkinson’s disease mouse model

Abstract Dysregulated T-cell responses and neuroinflammation are key contributors to neurodegeneration in Parkinson’s disease (PD). Modulation of regulatory T-cells (Tregs) to restore immune balance has therefore emerged as a potential neuroprotective strategy. In this study, we investigated whether systemic treatment with the tumor necrosis factor receptor type 2 (TNFR2) agonist NewSTAR2 enhances Treg function and mitigates neuroinflammation in a PD mouse model. We found that PD-derived Tregs maintain an intrinsic capacity to respond to TNFR2 stimulation, exhibiting increased activation and suppressive function. However, NewSTAR2 concurrently activated the pro-inflammatory immune compartment in the PD environment, thereby possibly counteracting potential neuroprotective effects. These findings suggest that PD-associated immune alterations redirect the overall response to TNFR2 stimulation away from a regulatory phenotype. Collectively, our results refine the current knowledge on immune dysregulation in PD and underscore the importance of disease context in the development of TNFR2-targeting therapies.