Type I interferon (IFN-alpha/Beta) is an important modulator of both innate and adaptive immunity and provides one of the first intracellular barriers to viral and bacterial infections. IFN-alpha/Beta is also used to treat such diseases as chronic hepatitis, multiple sclerosis, and a variety of neoplasias. These processes are not well understood because current mouse models fail to recapitulate many important aspects of IFN-alpha/Beta responses that operate in humans. For example, in humans, IFN-alpha/Beta promotes IFN-gamma secretion by activating a key transcription factor, Stat4. However, IFN-alpha/Beta does not induce Th1 development in the mouse because IFN-a/p does not activate Stat4 in murine T cells. Based on the importance of IFN-alpha/Beta in regulating both innate and adaptive immune responses and the species-specific nature of IFN-alpha/Beta signaling, the goals of this study are to fully characterize the CD4+ adaptive T cell response to IFN-alpha/Beta in human T cells. Induction of this pathway leads to unique immunological responses to pathogens that elicit IFN-alpha/beta production during infection in humans. Further, this pathway confers unique phenotypes and patterns of gene expression in human CD4+ T cells that are not found in mice.
In Aim 1 of this proposal, we will identify IFN-alpha/beta induced developmental pathways through gene expression profiling and analysis of cytokine expression patterns.
Aim 2 will characterize effector functions of IFN-alpha/Beta-driven T cells including cytolytic activity, inhibition of viral replication with the use of vaccinia virus, and support of B cell immunoglobulin secretion.
In Aim 3, we will determine the role that specific signaling pathways and transcription factors play in regulating IFN-alpha/beta-dependent T helper development. This study will provide a very important framework for understanding the link between innate and adaptive responses to pathogens that primarily induce IFN-alpha/Beta during initial periods of infection.
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