ORCID

http://orcid.org/0000-0001-5624-2488

Date of Award

Spring 5-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

In response to infection, antigen specific CD4 and CD8 T cells rapidly divide to provide help to the immune system and promote cytotoxicity of infected cells, respectively. Through this rapid division, CD4 and CD8 T cells maintain silencing of the opposing lineage’s genes, which is essential to acutely eliminating pathogens. However, not all pathogens are acutely eliminated even when silencing is maintained, and the pathogen persists in the presence of activated CD8 T cells. CD8 T cells chronically exposed to antigen are phenotypically different than CD8 T cells acutely exposed to antigen, but CD8 T cell still exert control over chronic infections and cancers. Two unanswered questions regarding the maintenance CD8 T cell responses are: 1. How do CD8 T cells maintain the silencing of alternative lineage genes through division in the periphery, and 2. How do these cells maintain viral control through chronic stimulation. To shed light on these questions, two specific aims were developed for this thesis. The first specific aim was to determine whether the epigenetic factor G9a is required to maintain silencing of helper lineage genes in proliferating CD8 T cells. To this end, genetic deletion of G9a in CD8 T cells resulted in de-repression of Cd4 and other helper T-related genes during lymphopenia- or tumor antigen-induced proliferation. In response to Listeria monocytogenes infection, G9a deficient CD8 T cells maintained silencing of Cd4. These data highlight that proliferating CD8 T cells employ multiple gene silencing mechanisms including G9a–mediated epigenetic modifications to maintain silencing of T helper-associated genes. The second specific aim of this study was to determine how increasing PI3K signaling affects the maintenance of a functional CD8 T cell pool during chronic viral stimulation. During chronic Lymphocytic choriomeningtis virus (LCMV) infection, overexpression of a constitutively active form of PI3K in CD8 T cells caused lethal immunopathology reminiscent of chronic infection of PDL1 knockout mice. Inducible overexpression of PI3K after CD8 T cell priming depleted the memory- and stem-like CD8 T cell pool, which is required to sustain the CD8 T cell response. These data highlight an epistatic relationship between PI3K and PD1 in chronic CD8 T cells, and inhibitory signals may protect the chronic CD8 T cell progenitors from depletion throughout the course of infection. Future work will determine whether the responsiveness of CD8 T cells to PI3K signaling or PD1 blockade requires the transcription factor AP4.

Language

English (en)

Chair and Committee

Takeshi Egawa

Committee Members

Paul Allen, Marco Colonna, Eugene Oltz, Haina Shin,

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