Date of Award

2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

E. J. Wherry

Abstract

Cytotoxic lymphocytes are central components of cellular immune responses to intracellular pathogens and malignancy. The transcriptional programs that support proper population dynamics for lifelong immunity are incompletely understood. Two T-box transcription factors, T-bet and Eomesodermin (Eomes), have critical roles in the development of natural killer cells and the differentiation of CD8+ T cells in response to acutely resolved infections. In both cases, these two factors support distinct but complementary cellular populations. In this thesis, we first used a recently generated reagent to examine and separate cellular populations with differential Eomes expression. We found that, while Eomes expression does not identify effector CD8+ T cells with enhanced cytotoxic potential, early Eomes expression does correlate with more efficient formation of long-lived, self-renewing central memory CD8+ T cells. This validated tool was then employed in our investigation into the population dynamics of CD8+ T cell responses during a chronic viral infection. While memory lymphocytes maintain lifelong immunity by slow self-renewal, chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling the regenerative capacity during chronic infection, however, are unknown. We demonstrate that two distinct states of virus-specific CD8+ T cells exist in chronically infected mice and humans. The opposing properties of renewal and differentiation of these CD8+ T cell populations are supported by the differential expression of T-box transcription factors, which cooperatively maintain the pool of antiviral CD8+ T cells during chronic viral infection. T-bethi cells have low intrinsic turnover but proliferate in response to persisting antigen, giving rise to Eomeshi terminal progeny. Genetic elimination of either subset results in failure to control chronic infection, suggesting that imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections. Furthermore, this work demonstrates new roles for T-bet and Eomes in CD8+ T cells regarding self-renewal and terminal differentiation, highlighting how T-box transcription factors can operate in exquisitely context-dependent manners.

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