The Adaptive Immune System and Parkinson's Disease Pathogenesis

The cause of neuronal death in Parkinson’s disease (PD) remains unknown, but multiple findings implicate peripheral T cells that infiltrate into the central nervous system (CNS). PD patients possess circulating T cells that are activated by antigenic epitopes derived from -Synuclein (-Syn) - a PD-associated protein. T cells are present in postmortem substantia nigra (SN) of PD patients about 10-fold higher than in age-matched controls. Whether these are autoimmune T cells, how they infiltrate into the CNS, and if they drive cellular damage and PD-like phenotypes is unknown. We hypothesize that neuroinflammation and neurodegeneration in PD is mediated by the entry of -Syn-specific T cells into the CNS via interactions with border associated macrophages (BAMs). This is based on our team’s findings that: 1) CD4+ T cell infiltration and MHC-II antigen presentation by BAMs (but not microglia) are required for dopaminergic (DA) neurodegeneration in an AAV - Syn overexpression mouse model; 2) active immunization with -Syn epitopes elicit proliferation of T cells that produce prodromal PD-like ENS symptoms associated with gut inflammation, constipation and neuronal loss; 3) neuropathological demonstration of increased T cell infiltration into human PD SN associated with increased proliferation of tissue resident T cells possessing a unique TCR repertoire. Here, we will: a) characterize routes of -Syn-specific T cells entry into the CNS after adoptive transfer and their roles in neuroinflammatory signatures of PD; b) determine the role of BAMs in antigen re-stimulation and CNS entry of -Syn-specific T cells; and c) analyze neurodegeneration due to -Syn-specific T cell - BAM interactions. We will use a novel adoptive transfer model by combining genetically-labelled -Syn-responsive Th17 and Th1 lymphocytes from a donor mouse immunized with -Syn antigenic epitopes with passive transfer into recipient naive -Syn overexpressing mice. We will examine T cell distribution into CNS parenchyma and borders (meninges, vessels and choroid plexus) via FACS and IF imaging to determine the timing and route of CNS entry and perform TCR sequencing to elucidate the clonality and antigen recognition of specific TCRs. We will compare the T cell phenotypes that enter the rodent CNS with those identified in PD post-mortem brain. In aim 2, we will examine myeloid cell activation after adoptive transfer of distinct T cell subtypes using IF and scRNA-seq to determine transcriptome changes in the mouse model. We will also determine if transient depletion of BAMs and repopulation from the periphery via bone marrow chimeras is critical for antigen re-stimulation and CNS entry of -Syn-specific T cells. Finally, we will compare the molecular changes in mice with those in human post-mortem brain. In aim 3, we will examine the molecular changes in neurons and CNS border cells (blood vessels, meninges and choroid plexus) in the adoptive transfer model. We will compare the effects on SN neuronal loss and striatal DA deficits in mice lacking the type II Interferon receptor in DA neurons. Overall this study will elucidate the role of distinct populations of -Syn-specific T cells and BAMs for PD pathogenesis. Project Number: 1R01NS147157-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: David Sulzer (+2 co-PIs) | Institution: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC, NEW YORK, NY | Award Amount: $627,103 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 AN-Z (55)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11281120