Analysis of the role of the transcription factor IRF4 for cytotoxic T lymphocyte effector function and memory development

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CD8+ T cells contribute to host defense during infection with intracellular pathogens, and in the elimination of tumor cells. After stimulation via their TCR, naïve CD8+ T cells differentiate into effector cytotoxic T lymphocytes (CTLs) which acquire the ability to kill target cells and into memory cells which are responsible for immunity to reinfection. The factors and mechanisms that drive the development of effector and memory CTLs are not completely understood. However, recent evidence suggests that both events are coordinated by a common transcriptional module for CD8+ T and B cells. Extensive studies in B-cells have shown that the transcription factor interferon regulatory factor 4 (IRF4) plays an essential role in B-cell effector differentiation and may be involved in this module. In contrast, in CD8+ T cells only a single report exists that analyzed CTL function in IRF4 deficient mice and suggested a critical role of IRF4 for CD8+ T cell effector development. To understand the mechanisms governing CTL differentiation, we intend to analyze the function of IRF4 in CD8+ T cells more closely in vitro and in vivo during the infection of mice with the intracellular bacterium Listeria monocytogenes. The results obtained by this project will provide deeper insights of the transcriptional network governing CD8+ T cell effector and memory differentiation. Improved understanding of the role of IRF4 could lead to new types of immunotherapy that modulate IRF4 levels to alter effector and/or memory CD8+ T cell differentiation.