Neurofibromin and IL-4 as Regulators of T Cell Development, Function and Homeostatis.

Abstract

The regulation of intracellular signaling is critical to the ability of a T cell to develop, survive, and function in an immune response. In this work, we examined the effect of T cell-specific deletion of the Ras GTPase-activating protein (RasGAP) neurofibromin (NF1) on T cell development and function. We have determined that NF1 has a non-redundant role in T cell development in the thymus as well as in peripheral T cell homeostasis. NF1-deficient naïve CD8+ T cells express higher amounts of the effector cytokine interferon-gamma (IFN-gamma) and the transcription factor Eomesodermin, and this is likely the reason for the ability of T cell-specific neurofibromin-deficient mice to respond more efficiently to Listeria monocytogenes infection in vivo.

We have also determined that the cytokine IL-4 is an inducer of IFN-gamma expression in wild-type CD8+ T cells. IL-4 directly induces transcription at the ifng locus, which is augmented by concomitant T cell antigen-receptor (TCR) stimulation, and is likely due to IL-4-mediated upregulation of the transcription factors Eomesodermin and T-bet. The effects of IL-4 on IFN-gamma expression in CD8+ T cells are mediated by Ras-ERK and PI3K signaling, with dependence on STAT6 activation when the TCR is activated concomitantly with the IL-4 receptor.

Finally, we show that the induced systemic loss of both NF1 and the related RasGAP RASA1 in adult mice promotes the development of T cell lymphoma. Lymphoma cells were found to populate all hematopoietic and were CD4+CD8+ CD25+TCR- cells of thymic origin. Tumor cells were also found to possess activating mutations in Notch1, a hallmark of both human and murine T cell acute lymphoblastic lymphoma/leukemia (T-ALL), in all but one instance of disease. Altogether, this work demonstrates the importance of regulation of signal transduction pathways in normal T cell function.