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 Ca(2+) entry through plasma membrane Ca(2+) channels, which is an indispensable step for T-cells to expand clonally and to acquire effector functions. The Ca(2+) channels are activated by depletion of Ca(2+) stores and are called Ca(2+) release-activated Ca(2+) (CRAC) channels. Ca(2+) influx through CRAC channels is also controlled, directly or indirectly, by K(+) channels, Ca(2+)-ATPases, mitochondria, endoplasmic reticulum and Ca(2+) buffers. We review the functional implications of these transporters, organelles and buffers and develop a model of Ca(2+) signal generation that depends mainly on their relative mutual localization. This model offers the possibility of controlling amplitude and kinetics of Ca(2+) signals in T-cells. Decoding of various Ca(2+) signals allows differential activation of the transcription factor families nuclear factor of activated T-cells (NFAT), nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Variation of amplitude and kinetics of Ca(2+) signals thus is an important mechanism for modulating the specificity of T-cell responses.