Summary/Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder, affecting over 1 million people in the U.S. alone. There are no therapies to stop its progression, likely due to our lack of understanding of the mechanisms underlying PD. Solid evidence has emerged indicating that the spreading of α-synuclein (α-syn) pathology across the brain and the presence of neuroinflammation play key roles. Propagation of α-syn aggregates along neural networks associates with the development of neuropathology and symptom worsening. Accumulation of α-syn aggregates is thought to increase neuroinflammation and neuroinflammation has been shown to promote α-syn aggregation, eventually leading to neuronal loss. It is also known that the immune system is activated in PD, featuring elevated pro-inflammatory cytokines in the brain, as well as activation of T cells and microglia. Notably, T cells can be found in the brains of PD patients and circulating T cell subsets are reduced in PD, indicating dysregulation of immune function. Reports also described changes in the ratio of specific subsets of circulating T cells in PD. Despite the growing body of evidence and the fact that such changes are key in inflammatory signaling, it remains unclear whether the reported changes in T cell populations affect the progressive increase in α-syn pathology and neurodegeneration. To help answer this question, we will use refined experimental models to define the role of specific subtypes of T cells in the development and spreading of PD-like α-syn pathology and associated neuropathology. In line with the premise that T cells are key in the pathogenesis of PD, our preliminary data show that when α- syn pathology is triggered in immunocompromised mice (lacking T cells, B cells and natural killer cells) the accumulation of α-syn pathology increases substantially. Accordingly, this increase was ameliorated upon T cell reconstitution. These data strongly support our hypothesis that T cells are involved in controlling the development of α-syn pathology. The objective of this project is to establish which T cell population (CD4+, CD8+ or Treg) can limit the spread of α-syn pathology, and modulate PD-like neuropathology (i.e., microgliosis, astrogliosis and dopamine neuron death) in a mouse model of PD. The proposed work combines the expertise of PD researchers (Brundin lab) and immunologists (Bettelli lab). First, the capacity of CD4+ and CD8+ T cells in altering the propagation of α-syn pathology will be tested using CD4 and CD8 knock-out (KO) mice combination with adoptive transfer of the individual populations in Tcrb KO mice (deficient in alpha/beta T-cell receptor). Second, the specific contribution of Treg cells will be established using a Foxp3 knock-in mice to determine changes in Treg populations (e.g., brain vs periphery). By defining which T cell subtypes are important for the development of α- syn pathology, strategies to control their function could poten...