Date of Award

Fall 12-22-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Cell & Molecular Biology

First Advisor

Michael R. Betts

Abstract

CD8+ T cells are often referred to as cytotoxic T lymphocytes because of their ability to induce the apoptosis of cells infected with an intracellular pathogen, thereby limiting the spread of an infection to previously uninfected cells. CD8+ T cells produce many proteins - including perforin, various granzymes, and granulysin - that are responsible for inducing target cell cytolysis. These cytolytic proteins are found pre-packaged into secretory granules within many resting CD8+ T cells, but their de novo synthesis can also occur after activation. In the setting of HIV infection, a rare group of HIV-positive patients, termed elite controllers (EC), naturally control HIV viremia to virtually undetectable levels without the intervention of drug therapy. Some evidence has implicated HIV-specific CD8+ T cells in achieving or maintaining this virologic control; however, the mechanism(s) to explain these findings remains largely undefined. In this work, we report that HIV-specific CD8+ T cells from EC demonstrated a superior ability to express perforin and granzyme B after activation compared to patients with progressive disease. Therefore, HIV-specific CD8+ T cells from EC possessed a greater cytotoxic potential by expressing higher levels of two principal cytolytic mediators, which may at least partially explain the ability of EC to suppress the replication of HIV in vivo. One critical upstream regulator of effector functionality and differentiation is the T-box transcription factor T-bet. We demonstrated a clear link between levels of T-bet and the presence of perforin and granzyme B within human CD8+ T cells. Notably, HIV-specific CD8+ T cells from EC expressed higher amounts of T-bet than progressors, suggesting that therapeutic modulation of T-bet may restore the cytolytic potential that is deficient among patients with uncontrolled viremia. Collectively, our results imply that the underlying defect(s) in effector function by HIV-specific CD8+ T cells from progressors lie not in the cytolytic proteins themselves, but rather in the elements controlling their expression, including T-bet.

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