Ca²⁺ Microdomains in T-Lymphocytes

Early Ca²⁺ signaling is characterized by occurrence of Ca²⁺ microdomains formed by opening of single or clusters of Ca²⁺ channels, thereby initiating first signaling and subsequently activating global Ca²⁺ signaling mechanisms. However, only few data are available focusing on the first seconds and minutes of Ca²⁺ microdomain formation and related signaling pathways in activated T-lymphocytes. In this review, we condense current knowledge on Ca²⁺ microdomain formation in T-lymphocytes and early Ca²⁺ signaling, function of Ca²⁺ microdomains, and microdomain organization. Interestingly, considering the first seconds of T cell activation, a triphasic Ca²⁺ signal is becoming apparent: (i) initial Ca²⁺ microdomains occurring in the first second of T cell activation, (ii) amplification of Ca²⁺ microdomains by recruitment of further channels in the next 5-10 s, and (iii) a transition to global Ca²⁺ increase. Apparently, the second messenger nicotinic acid adenine dinucleotide phosphate is the first second messenger involved in initiation of Ca²⁺ microdomains. Ryanodine receptors type 1 act as initial Ca²⁺ release channels in CD4⁺ T-lymphocytes. Regarding the temporal correlation of Ca²⁺ microdomains with other molecular events of T cell activation, T cell receptor-dependent microdomain organization of signaling molecules Grb2 and Src homology [SH2] domain-containing leukocyte protein of 65 kDa was observed within the first 20 s. In addition, fast cytoskeletal changes are initiated. Furthermore, the involvement of additional Ca²⁺ channels and organelles, such as the Ca²⁺ buffering mitochondria, is discussed. Future research developments will comprise analysis of the causal relation between these temporally coordinated signaling events. Taken together, high-resolution Ca²⁺ imaging techniques applied to T cell activation in the past years paved the way to detailed molecular understanding of initial Ca²⁺ signaling mechanisms in non-excitable cells.