Neutrophil IFN-gamma in host defense and inflammation

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 DESCRIPTION (provided by applicant): IFN- is a key cytokine that mediates host resistance to a variety of intracellular pathogen. Until recently, it was largely acknowledged that lymphoid cells are the sole sources for IFN-. We have recently established that neutrophils are an emerging cellular source of IFN-, a key cytokine that mediates host defense to Toxoplasma gondii and other intracellular pathogens. Production of IFN-by neutrophils, in contrast to lymphoid cells, is Toll-like receptor (TLR) and IL-12-independent and the events associated with IFN- production by neutrophils are not understood. We have also observed that neutrophils express IFN-during their lineage development in the bone marrow niche independently of microbes. IFN- accumulates in neutrophilic granules and is released upon induction of neutrophil degranulation. We propose to build upon these findings to gain a deeper understanding of how neutrophil-derived IFN- expression is regulated, and to investigate the physiological significance of neutrophil-derived IFN- in mouse and human models of toxoplasmosis. In Aim 1, we will identify neutrophil precursors involved in IFN- production in naïve and Toxoplasma gondii-infected mice and determine the transcription factors that regulate IFN- production in human and mouse neutrophil. In Aim 2, we will use mice harboring neutrophil-specific IFN- deficiency to test the hypothesis that neutrophil-derived IFN-coordinates innate and adaptive immune responses to Toxoplasma gondii. These studies will advance our understanding of how human and mouse innate immune systems