Regulation of TCR signaling by a novel enzyme activity.

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DESCRIPTION (provided by applicant): The T cell auto-reactivity that lies at the heart of many autoimmune diseases arises from the very properties that allow T cells to mount an effective immune response. Thus, to understand the etiology of different autoimmune diseases will require a thorough and integrated understanding of the mechanisms that control T cell activation. The long-term objective of my research is to understand the biochemistry of T cell reactivity. Currently, my laboratory is studying how two related proteins, Sts-1 and Sts-2, act in concert to negatively regulate T cell signaling pathways. The role of Sts-1 and -2 in controlling TCR signaling pathways was revealed by a strain of mice engineered to lack the Sts genes. T cells from Sts- 1/2-/- mice dramatically hyper-proliferate in response to TCR stimulation. This hyper-proliferative phenotype is accompanied by increased activation of signaling pathways downstream of the TCR, elevated levels of cytokine production, and increased susceptibility of Sts-1/2-/- mice to autoimmunity in a mouse model of multiple sclerosis. In our ongoing effort to characterize the functions of the Sts proteins, we recently discovered that Sts-1 has a novel and potent enzyme activity. This activity derives from an evolutionarily conserved region within the protein and our recent data indicates that it plays an essential role in the ability of Sts-1 to regulate TCR signaling pathways. Sts-1 is sufficiently dissimilar to other known enzymes to make it a novel and unique phosphatase. In addition, the connection between Sts-1 catalytic activity and regulation of T cell activation in unknown and unexplored. The experiments outlined in this proposal are designed to shed light on these areas. Our Specific Aims are: 1. To determine the structural features that define and regulate Sts-1 catalytic activity. 2. To determine the role of Sts-1 phosphatase activity in regulating Zap-70 signaling. We will use some recently developed protocols to accomplish our goals. Completion of the studies described herein will help us build a model of how Sts-1 cooperates with Sts-2 and other intracellular signaling mechanisms to control T cell reactivity. It is our hope that a broad, integrated understanding of all the mechanisms that control T cell activation will translate into therapies that prevent the onset of a variety of autoimmune diseases. Autoimmune diseases arise when normal regulatory mechanisms within the immune system fail. Developing therapies that will prevent or cure autoimmune diseases will require a thorough and integrated understanding of the mechanisms that control the immune response. This project focuses on understanding the function of a novel protein that participates in the regulation of T cell activation.