Calcium-dependent activation of T-lymphocytes

Activation of T-lymphocytes requires stimulation of T-cell receptors (TCR) and co-stimulatory signals. Among different signalling cascades, TCR engagement induces Ca2+ entry through plasma membrane Ca2+ channels, which is an indispensable step for T-cells to expand clonally and to acquire effector functions. The Ca2+ channels are activated by depletion of Ca2+ stores and are called Ca2+ release-activated Ca2+ (CRAC) channels. Ca2+ influx through CRAC channels is also controlled, directly or indirectly, by K+ channels, Ca2+-ATPases, mitochondria, endoplasmic reticulum and Ca2+ buffers. We review the functional implications of these transporters, organelles and buffers and develop a model of Ca2+ signal generation that depends mainly on their relative mutual localization. This model offers the possibility of controlling amplitude and kinetics of Ca2+ signals in T-cells. Decoding of various Ca2+ signals allows differential activation of the transcription factor families nuclear factor of activated T-cells (NFAT), nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Variation of amplitude and kinetics of Ca2+ signals thus is an important mechanism for modulating the specificity of T-cell responses.