Pathophysiological alterations of regulatory T cells in Parkinson's disease and generation of aSyn-CAR-Tregs as a novel therapeutic approach.
I DOMÍNGUEZ-GARCÍA(1,2) E GARCÍA-GUERRERO(1) J A PÉREZ-SIMÓN(1) J J TOLEDO-ARAL(1,2) A RODRÍGUEZ-GIL(1,2) J VILLADIEGO(1,2)
1:Instituto de Biomedicina de Sevilla (IBiS); 2:Universidad de Sevilla
Parkinson's disease (PD) is characterized by the progressive degeneration of nigrostriatal dopaminergic neurons, alpha-synuclein (aSyn) aggregation and chronic neuroinflammation. Recent studies show that aSyn aggregation leads to T-cell-mediated activation of the immune response, playing a major role in the regulation of the neuroinflammatory response and neurodegeneration. In particular, regulatory T cells (Tregs), which are the main physiological suppressors of the immune system, have been shown to be altered in PD patients, and their adoptive transfer reduces the neuroinflammation and protects against dopaminergic degeneration in preclinical PD models. In this work, we carried out a functional characterization of Tregs in murine models of PD. Interestingly, we found that the PD-associated mutation of LRRK2 (G2019S) decrease the population of C62L+ Tregs and the expression of CD73, both factors related with the maturity state and the suppressive capability of Tregs. In addition, with the aim to enhance the immunosuppressive effect of Tregs and to direct them to the damaged nigrostriatal pathway, we have generated CAR-T against aSyn aggregates (aSyn-CAR-T) that specifically recognize pathological aggregates of human aSyn and promote the activation of T cells. Moreover, experiments of adoptive transfer in a human-aSyn mouse PD model indicate that the transferred aSyn-CAR-T-cells remain in peripheral blood and are able to infiltrate the damaged nigrostriatal pathway. The identification of functional Tregs alterations associated with PD and the preclinical validation of the aSyn-CAR-Tregs outcome would be important steps to design new Tregs-based therapies in PD.