All ETDs from UAB

Advisory Committee Chair

Allan J Zajac

Advisory Committee Members

Scott R Barnum

Stephen A Watts

Document Type

Thesis

Date of Award

2011

Degree Name by School

Master of Science (MS) College of Arts and Sciences

Abstract

During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of interleukin (IL)-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of IFN-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce interferon-gamma (IFN-γ) and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. This unresponsiveness was associated with downregulation of the IL-18 receptor (R) on exhausted T cells. Although IL-18R expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18R-low exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18R downregulation, we tracked the fate of IL-18R-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18R-/- cells were preferentially lost during the contraction phase of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18R-high memory cells upregulated CD25 and produced IFN-γ, the IL-18R-low exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial coinfections.

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