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Key Words T cell activation, store-operated calcium channel, 'P3 receptor, calcium ATPase, mitochondria, calcium oscillations
* Abstract Elevation of intracellular free Ca2+ is one of the key triggering signals for T-cell activation by antigen. A remarkable variety of Ca2+ signals in T cells, ranging from infrequent spikes to sustained oscillations and plateaus, derives from the interactions of multiple Ca2+ sources and sinks in the cell. Following engagement of the T cell receptor, intracellular channels (IP3 and ryanodine receptors) release Ca2+ from intracellular stores, and by depleting the stores trigger prolonged Ca 21 influx through store-operated Ca2+ (CRAC) channels in the plasma membrane. The amplitude and dynamics of the Ca2+ signal are shaped by several mechanisms, including K+ channels and membrane potential, slow modulation of the plasma membrane Ca 21-ATPase, and mitochondria that buffer Ca 21 and prevent the inactivation of CRAC channels. Ca2+ signals have a number of downstream targets occurring on multiple time scales. At short times, Caz+ signals help to stabilize contacts between T cells and antigen-presenting cells through changes in motility and cytoskeletal reorganization. Over periods of minutes to hours, the amplitude, duration, and kinetic signature of Ca2+ signals increase the efficiency and specificity of gene activation events. The complexity of Ca2+ signals contains a wealth of information that may help to instruct lymphocytes to choose between alternate fates in response to antigenic stimulation.
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A rather large number of pathways are now known to participate in the generation of Ca2+ signals in T cells following contact with antigen. Interactions among these help to generate a diversity of complex Ca2+ signaling patterns, which may transmit specific types of information to the cell. Though substantial progress has been made in cloning some of the molecules involved in Ca2+ signaling, identifying the molecular basis of the CRAC channel and its mechanism of regulation by store content remains a central but elusive goal. The spatial distributions of Ca2+ sources and sinks in T cells are also largely unknown, but they may be critical in establishing specific interactions that control patterns of Ca2+ signaling. The fine structure of Ca"+ signals appears to change as T cells mature and as mature cells undergo further differentiation to become Thl, Th2, or memory cells (14,...