The importance of Ca²⁺ microdomains for the adaptive immune response

Calcium signaling stands out as the most widespread and universally used signaling system and is of utmost importance for immunity. Controlled elevations in cytosolic and organellar Ca²⁺ concentrations in T cells control complex and essential effector functions including proliferation, differentiation, cytokine secretion, and cytotoxicity, among others. Additionally, disruptions in Ca²⁺ regulation in T cells contribute to diverse autoimmune, inflammatory, and immunodeficiency conditions. Among the initial intracellular signals, which occurring even before T cell receptor (TCR) stimulation are highly localized, spatially and temporally restricted so-called Ca²⁺ microdomains, caused by adhesion to extracellular matrix proteins (ECM proteins). The Ca²⁺ microdomains present both before and within the initial seconds following TCR stimulation are likely to play a crucial role in fine-tuning the downstream activity of T cell activation and thus, shaping an adaptive immune response. In this review, the emphasis is on the recent advances of adhesion-dependent Ca²⁺ microdomains (ADCM) in the absence of TCR stimulation, initial Ca²⁺ microdomains evoked by TCR stimulation (TDCM), the downstream signaling processes as well as possible therapeutic targets for interventions.