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ORCID

https://orcid.org/0000-0002-5979-9406

Date of Award

Summer 8-15-2018

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Cytotoxic CD8+ T cells (CTLs) play a critical role in protective immunity against viruses, a fact underscored by the evolution of viral CTL evasion mechanisms. For instance, many viruses commonly target the major histocompatibility complex class I (MHCI) antigen presentation pathway to prevent CTLs from recognizing infected cells. A striking example of this is cowpox virus (CPXV), which interferes with MHCI antigen presentation through two distinct mechanisms. One mechanism of CPXV-mediated MHCI inhibition is to retain MHCI molecules in the endoplasmic reticulum (ER). The second mechanism is to prevent antigen peptide loading onto MHCI molecules. When combined these mechanisms result in potent inhibition of MHCI antigen presentation and effective evasion of CPXV-specific CTL responses in vivo. However, it is unclear how viral MHCI inhibition affects the CTL repertoire and the subsequent development of memory CD8+ T cells. Furthermore, the effects of viral MHCI inhibition on local memory CD8+ T cell responses during peripheral CPXV infection has not been examined. To explore these issues, I used a CPXV murine infection model to compare CD8+ T cell responses against CPXV and a CPXV mutant that is incapable of inhibiting MHCI antigen presentation. Herein, I demonstrate that viral MHCI inhibition affects the local CTL and memory CD8+ T cell repertoire in specific niches. Primary anti-CPXV responses and memory responses were shaped by antigen abundance and CD8+ T cell cross-competition for viral peptide-MHCI complexes on the cell surface of antigen presenting cells (APCs), respectively. Additionally, I show that the overall quality and quantity of CTL and memory CD8+ T cells is unaffected by viral MHCI inhibition following CPXV infection. Finally, I determined that viral MHCI inhibition contributes to evasion of local memory CD8+ T cell responses. Collectively, the results of these studies provide insight on determinants that influence the anti-viral CD8+ T cell repertoire, local memory formation, and local memory responses.

Language

English (en)

Chair and Committee

Wayne M. Yokoyama

Committee Members

Adrianus C. Boon, Brian T. Edelson, L. D. Sibley, Haina Shin,

Comments

Permanent URL: 2019-08-16

Available for download on Friday, August 16, 2019

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