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.
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