In addition to regulating electrical activity in the nervous system, ion channels mediate very different cellular mechanisms within the immune system. The earliest events signaling the binding of antigen to surface receptors in T lymphocytes and mast cells include the activation of ion channels and a rise in cytosolic [Ca2+]i. The """"""""[Ca2+]i signal"""""""" is generated by the opening of ion channels, and links membrane receptors to gene expression, lymphokine secretion and cell proliferation essential to the immune response. With emphasis on a single-cell approach, the investigators are proposing video-imaging and patch-clamp experiments to clarify mechanisms which link membrane receptors to effector functions such as cell proliferation, gene expression, cell motility, and secretion of immunomodulatory molecules. The proposed experiments on T lymphocytes are divided into two sections corresponding to the sequence of events following antigen stimulation: (1) intracellular signaling from the engagement of membrane receptors to the [Ca2+]i signal; (2) activation of the interleukin-2 gene and other signaling pathways by the rise in [Ca2+]i. One goal of this project is to apply optical techniques to investigate [Ca2+]i signaling, motility, and gene expression in primary T-cells stimulated by physiological ligands. The investigators will use reporter genes to visualize T-cell activation dynamically in order to relate membrane and second-messenger mechanisms to effector function. They are investigating interactions between cells during antigen presentation, as well as intracellular signaling mechanisms that link membrane receptors with gene expression.
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