The T Cell Response In A Mouse Model Of Multiple System Atrophy

Authors

• Nicole Jane Corbin-Stein, University of Alabama at Birmingham

Advisor(s)

Ashley Harms

Committee Member(s)

Andrew Arrant
Chander Raman
David Standaert
Laura Volpicelli-Daley

School

Joint Health Sciences (Interdisciplinary)

Document Type

Dissertation

Department (new version)

Neurobiology

Date of Award

9-9-2024

Abstract

Multiple System Atrophy (MSA) is a fatal and rare demyelinating synucleinopathy, characterized by the accumulation of alpha-synuclein (α-syn) in glial cytoplasmic inclusions (GCIs) within oligodendrocytes. This condition is marked by neuroinflammation, demyelination, and neurodegeneration in areas showing GCI pathology, involving antigen presentation by myeloid cells and infiltration of CD4+ and CD8+ T cells. Despite strong evidence of neuroinflammation in post-mortem MSA tissue, the specific mechanisms driving the disease pathogenesis remain elusive. In prior research using the Olig001-SYN mouse model, which involves the modified AAV vector, it was shown that depleting CD4+ T cells can reduce neuroinflammation and demyelination. Notably, this study also found that levels of the pro-inflammatory cytokine, interferon gamma (IFNγ), were elevated when α-syn was present in oligodendrocytes. Building on this, our current study using the same Olig001-SYN mouse model demonstrates that depleting IFNγ, through both genetic and pharmacological methods, can effectively prevent neuroinflammation, demyelination, and ultimately, neurodegeneration. Moreover, using an IFNγ reporter mouse, we identified CD4+ T cells as the primary producers of IFNγ during MSA. IFNγ is known to interact with CD8+ T cells, enhancing their ability to induce apoptosis in infected cells. We investigated the role of CD8+ T cells in MSA and found that, similar to post-mortem MSA tissues, there is an infiltration of CD8+ T cells in the brain parenchyma with α-syn overexpression in oligodendrocytes. Interestingly, the absence of CD8+ T cells did not prevent demyelination or neurodegeneration. However, at earlier stages, their absence actually exacerbated neuroinflammation and demyelination. CD8+ T cells in the striatum during disease were identified as tissue resident memory (Trm) cells, indicating their role as long-term residents in the tissue. Our findings suggest that MSA progression is driven predominantly by IFNγ rather than by CD8+ T cells. This supports the notion that MSA is a CD4+ T cell-driven disease, specifically mediated by their Th1 subtype, rather than by the cytotoxic actions of CD8+ T cells.

ProQuest ID

https://proquest.com/docview/3101940325