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    Catherine Hartzell.
    T-cell receptor (TCR) binding to peptide-MHC (pMHC) on an antigen-presenting cell initiates a signaling cascade leading to calcium entry through calcium release-activated calcium (CRAC) channels. The role of calcium in activation of gene transcription programs essential for T-cell activation has been well studied, but effects of calcium on proximal signaling events remain poorly understood. The broad aim of my thesis is to better understand how calcium influx influences formation of a highly ordered signaling interface between the T cell and antigen-presenting cell known as the immune synapse. At the synapse, actin reorganizes into a concentric lamellipod (LP) and lamella (LM), and retrograde actin flow supports sustained signaling by the TCR. While the CRAC channel components STIM1 and Orai1 are known to localize to the synapse, how this occurs and their influence on synapse formation and function are unknown. In the first chapter of this thesis, I introduce to the structure and function of the immune synapse and describe what is known about the mechanisms driving actin remodeling and calcium influx at the synapse. In the second chapter, I investigate the mechanisms that control localization of CRAC channels to the immune synapse and the effects of calcium influx on actin organization and dynamics at the synapse. Using an in vitro model of the synapse, we find that retrograde actin flow corrals the ER and STIM1/Orai1 complexes to the center of synapse and that calcium influx through CRAC channels is required for creating a distinct LP and LM and for driving retrograde flow. calcium mediates this effect by promoting actin depolymerization and restricting polymerization to the distal edge of the LP. These results uncover a new role of calcium as a master regulator of actin organization and dynamics at the synapse, and reveal a positive feedback loop in which calcium influx promotes TCR function through its effects on actin dynamics. In the third and final chapter, I discuss the physiological implications of our findings as they relate to T-cell signaling and suggest future studies to probe role of calcium influx in T cell activation.
    Digital Access   2015