ORCID

http://orcid.org/0000-0002-6397-1205

Date of Award

Spring 5-15-2022

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 transient antigen presence in the context of acute infections or vaccinations, antigen-specific naïve T cells clonally expand and differentiate. Most of the expanded cells undergo terminally differentiation and die following antigen clearance to re-establish immune homeostasis. In contrast, when the pathogen persists, such as in the context of chronic viral infections or anti-tumor immunity, while T cells undergo alternative differentiation known as exhaustion due to their reduced functionality, T cells still contribute to pathogen control and its response is sustained for longer duration due to unknown mechanisms. The goal of my thesis work is to understand how protective T cell response is sustained at the cellular levels and molecular levels for CD8 T cells and CD4 T cells in the presence of persistent antigens. The main model used is the mouse chronic lymphocytic choriomeningitis virus (LCMV-clone 13, c13) infection model, which causes viremia that lasts 3-4 months in immunocompetent mice and is subsequently resolved in a manner dependent on CD4 and CD8 T cells. In the analyses of CD8 T cell responses, I identified previously undescribed populations of CD8 T cells that express the chemokine receptor CX3CR1 and further segregated into two populations based on expression of the inhibitory receptor TIM3. CX3CR1+ TIM3+ cells, despite the expression of inhibitory receptors, maintain proliferative states and express effector molecules, thus contributing to antiviral responses to the persisting virus. In contrast, the TIM3– CX3CR1+ CD8 T cells are quiescent, require the transcription factor T-bet, express low but significant levels of TCF-1, and act as immediate precursors for the TIM3+ CX3CR1+ CD8 T cells. These findings reveal hierarchical differentiation of exhausted CD8 T cells which transit from the previously reported TCF-1hi stem-like progenitor (TPEX) state, to T-bethi intermediate progenitor (TIM3+ CX3CR1+) state, to activated effector (TIM3+ CX3CR1+) state, which mediates sustained CD8 T cell immunity to persistent viral infection. In studies of CD4 T cell responses, I demonstrated that in addition to the differentiated TH1 and follicular helper (Tfh) cells, activated CD4 T cells also differentiate into memory-like cells in a BCL6-dependent manner. While the initial TH1 cells and Tfh cells are generated through independent developmental pathways directly from naïve T cells, as infection persists, TH1 cells and Tfh cells are both generated from this newly identified memory-like cells, which is required to maintain both TH1 and Tfh responses for prolonged duration. In response to tumors, an analogous CD4 T cell population develops in draining lymph nodes. These findings reveal the heterogeneity and plasticity of CD4 T cells upon encountering persistent antigen and highlights their population dynamics through a stable and bipotent intermediate state.

Language

English (en)

Chair and Committee

Takeshi Egawa

Committee Members

Chyi-Song Hsieh

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