Wei Su

Date of Award

11-2021

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Neurosciences

Research Advisor

Hongbo Chi, PhD

Committee

Yongqiang Feng, PhD Terrence L. Geiger, MD, PhD Francesca-Fang Liao, PhD Junmin Peng, PhD Gerard P. Zambetti, PhD

Keywords

Adaptive, Autoimmunity, CD8, Inflammation, Neuroinflammation, Treg

Abstract

Inflammation is essential for the clearance of pathogens and to facilitate healing of damaged tissue. However, this process must be controlled to limit immunopathology. Cell-intrinsic effects of inhibitory and signaling molecules are known to maintain quiescence and prevent effector differentiation and inflammation. Moreover, specific populations of immune cells exert cell-extrinsic effects for immunosuppression. Therefore, studies on the immunosuppressive functions of these cell populations will provide a better understanding of how inflammation is regulated and how its dysregulation causes human disease. Additional insights in this area may uncover novel targets to be manipulated for therapeutic benefit in autoimmune and inflammatory disorders, such as neurodegenerative diseases.

Foxp3-expressing regulatory T (Treg) cells are specialized immunosuppressive cells that establish immune tolerance to prevent the development of autoimmune and other inflammatory diseases, with effector-Treg (eTreg) cells playing a pivotal role. Recently, cellular metabolism has emerged as a mediator to enforce Treg-cell function and heterogeneity. In Chapter 3, we used genetic and pharmacological tools to demonstrate that isoprenoid-dependent posttranslational lipid modifications dictate eTreg-cell accumulation and function by intersecting with T cell receptor (TCR)-induced intracellular signaling. We showed that isoprenoids are essential for activated Treg-cell suppressive activity, and Treg cell-specific deletion of the enzymes that mediate farnesylation and geranylgeranylation (encoded by Fntb and Pggt1b, respectively) leads to a reduction of eTreg cells and the development of fatal autoimmunity. In Chapter 4, we further explored the mechanistic role of protein prenylation in the regulation of eTreg cells by performing a comprehensive analysis of protein prenylation-dependent molecular signaling in eTreg-cells. Specifically, we found that Fntb drives eTreg-cell maintenance by promoting mTORC1 activity-dependent proliferation and ICOS-mediated cellular fitness. In contrast, Pggt1b orchestrated transcriptional programming by TCR stimulation and Rac signaling to establish eTreg-cell differentiation and immune tolerance. Therefore, our results reveal a bidirectional interplay between immune signals, metabolism-mediated posttranslational modifications, and intracellular signaling for the differentiation and maintenance of eTreg cells.

Neuroinflammation is also a feature of neurogenerative diseases, but the underlying cellular mechanisms that limit inflammation in neurodegenerative diseases are largely unknown. In Chapter 5, using single cell RNA-sequencing (scRNA-seq) of immune cells in a mouse model of neurodegeneration (specifically, Alzheimer’s disease AD), we found that CD8 T cells accumulated in the brain parenchyma. These CD8 T cells had tissue resident memory-associated features and appeared to retain functionality. Importantly, T cell ablation was found to exacerbate disease-associated deposition of Beta- amyloid (A-Beta) and cognitive decline in a mouse model of AD. Moreover, in the absence of T cells, microglia acquired proinflammatory features and clustered in regions near A-Beta plaques, features associated with more severe disease. Collectively, these results suggest that T cells are critical to restrain microglia activation and limit neurodegeneration-associated pathologies in a murine model of AD.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

http://orcid.org/0000-0003-4165-8776

DOI

10.21007/etd.cghs.2021.0546

Additional Files
2021-017-Su-DOA.pdf (241 kB)
Declaration of Authorship
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