Myosin Motors in T cell Synapse Formation and Activation

University Of California San Francisco, San Francisco CA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Cell-cell interactions are of critical importance for expanding the range of the immune response in order to control infection. Yet, the mechanisms that control cell-cell contacts and receptor movement in the immune system remain cryptic. Using high-speed video microscopy, we have been able to demonstrate T cell receptor clustering followed by coalescence of these clusters into the central "synapse". Through simultaneous imaging of intracellular calcium levels, it has become apparent that while initial microclusters are associated with the onset of signaling, a program of cellular re-polarization is necessary for the formation of the central synapse structure and for sustained signaling. The overall goal of my research is to define spatial and temporal maps of the initiating events of immune recognition. The hypothesis underlying this project is that cellular myosin motors triggered by initial TCR signals are crucial for polarization of key membrane receptors into signaling complexes. The specific aims of this project are: 1. To define the myosin family members that are uniquely responsible for synapse formation in T cells, using biochemistry, in situ localization techniques and dominant negative mutations. 2. To determine the biochemical roles for myosins in T cell signaling by examining the interaction partners and phosphorylation of myosins upon TCR ligation. 3. To define the overlapping role of myosin-motors with signaling mediated by costimulatory signals and with signaling mediated by chemokines. These studies will not only provide fundamental information about the initial steps in lymphocyte activation, but may also lead to clues about ways to manipulate T cell responses in vitro and in vivo.