Date of Award

2022

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Edward J. Usherwood

Abstract

CD8 T cells are potent immune effector cells capable of vast clonal expansion and clearance of infected or cancerous cells. After control of the pathogenic insult, CD8 T cells develop into quiescent, long-lived memory populations that are poised to mediate rapid protection upon reencounter with cognate antigen. These properties make control of CD8 T cell responses a highly desirable outcome of vaccine strategies and immunotherapy. Therefore, understanding how the effector function and memory differentiation of CD8 T cells are controlled at a molecular level is of great importance. In the context of infection with gammaherpesviruses (γHV), which form a latent infection that persists for the life span of the host, CD8 T cells play a vital role in control of γHV associated lymphomagenesis. The following studies utilize murine gammaherpesvirus (MHV)-68 and a novel model of γHV-associated B cell lymphoma, EM61 to dissect the mechanisms of CD8 T cell mediated control of γHV associated lymphomagenesis. These studies indicate γHV-specific CD8 T cells control EM61 through mechanisms that partially overlap with those used to control viral replication, however, we note important differences as well. We additionally describe γHV-specific, tissue-resident, memory CD8 T cells (TRM) that form after infection with MHV-68. In the absence of CD4 T cell help, which causes reactivation of γHV during latency, the γHV-specific TRM compartment exhibits changes that are distinct from those observed in the context of acute viral infection. Additional work focused on the molecular control of CD8 T cells by the BTB-ZF family transcription factor (TF), Zbtb20, which restricts CD8 T cell memory differentiation. Using single cell techniques, we identify programs of transcriptional and epigenetic regulation associated with memory CD8 T cell differentiation that underly enhanced memory cell formation in the absence of Zbtb20. Furthermore, using a sensitive technique to interrogate Zbtb20-DNA binding, we describe DNA motifs and genomic annotations from the direct genomic targets of Zbtb20 in CD8 T cells. Together, this work provides new knowledge relevant to the response and control of CD8 T cells to infection and cancer.

Original Citation

Preiss, N. K. et al. Control of B Cell Lymphoma by Gammaherpesvirus-Induced Memory CD8 T Cells. The Journal of Immunology 205, 3372–3382 (2020).

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