Author ORCID Identifier

https://orcid.org/0000-0003-1109-5378

Date of Graduation

2024

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Microbiology, Immunology, and Cell Biology

Committee Chair

Gordon Meares

Committee Co-Chair

Candice Brown

Committee Member

Candice Brown

Committee Member

Jonathan Busada

Committee Member

Courtney DeVries

Committee Member

Jennifer Franko

Abstract

Multiple sclerosis (MS) is a cell-mediated, demyelinating autoimmune disease that affects the central nervous system (CNS). T helper (Th) 17 cells mediate the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis (EAE), in part by infiltrating the CNS and interacting with astrocytes, a resident glial cell. Astrocytes are central to coordinating several inflammatory processes in the CNS and can respond to cytokines and chemokines produced by encephalitogenic Th17 cells. Pathogenesis of MS and EAE requires the infiltration of immune cells from the periphery, including autoreactive T cells, B cells, monocytes, and neutrophils, that lead to neuroinflammation, demyelination, and neuronal damage. This work investigates the direct impact of pathogenic Th17 cells on astrocytes utilizing both in vitro and in vivo models. Here, we have generated myelin oligodendrocyte glycoprotein (MOG)-specific Th17 cells, confirmed their cytokine production profile, and demonstrated their capacity to reprogram astrocytes by inducing transcriptional changes through a Janus kinase (JAK)1-dependent mechanism. These reprogrammed astrocytes displayed increased expression of chemokines and cytokine receptors, and interferon-related genes, and a decreased expression of cilia-related genes. Moreover, the gene expression in the interferon-related genes and cilia-related genes were found to be JAK1-dependent. Additionally, we observed region-specific astrocyte heterogeneity in cell surface cytokine receptors, including receptors for TGFβ, IL-10, IL-1, IL-17, IFN-γ, and TNF-α. These receptors exhibited dynamic regulation throughout the course of EAE. Our findings reveal that Th17 cells influence the neuroinflammatory environment through reprogramming astrocytes, revealing the dynamic regulation of cytokine receptors on astrocytes during EAE, and suggesting both pro- and anti-inflammatory roles. We further describe a subset of astrocytes that co-express the TGFβ and IL-10 receptors, indicating a potential anti-inflammatory subpopulation. Overall, our work provides a deeper understanding of the molecular mechanisms underlying neuroinflammation by elucidating the intricacies between Th17 cells and astrocytes, emphasizing the potential of astrocytic reprogramming, and expanding the current knowledge on astrocyte diversity.

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