Paley, Michael Alexander, "Transcriptional Control And Population Dynamics Of Antiviral Cd8+ T Cell Responses " (2012). Publicly Accessible Penn Dissertations. Paper 682. Transcriptional Control And Population Dynamics Of Antiviral Cd8+ T

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 infecte