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. 2020 Feb 25;11:301. doi: 10.3389/fimmu.2020.00301

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Copyright © 2020 Häusler, Torke and Weber.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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T cell receptor signaling and calcium. After stimulation of the T cell receptor (TCR), the signal is relayed via immunoreceptor tyrosine-based activation motifs (ITAM) leading to the recruitment of zeta-activated protein 70 (ZAP70) and the phosphorylation of linker for activation of T cells (LAT). LAT recruits SH2-domain containing leucocyte protein of 76 kDa (SLP-76) which activates Interleukin-2 inducible tyrosine kinase (ITK). Subsequently, phospholipase C gamma 1 (PLC-γ1) creates diacylglycerol (DAG) and inositol triphosphate (IP₃) by cleaving phosphatidylinositol triphosphate (PIP₂). DAG activates protein kinase C (PKC), IP3 stimulates a calcium release from the endoplasmic reticulum (ER) via the IP3 receptor (IP3R). This calcium release induces the interaction of stromal interaction molecule 1 (STIM1) with CRAC modulator 1 (CRACM1). In addition membrane-bound channels from the transient receptor potential (TRP) family, P2X receptors or voltage-gated calcium-channels (Ca_v) contribute to calcium mobilization. The resulting calcium elevation activates several signaling proteins such as calcineurin and its target nuclear factor of activated T cells (NFAT), nuclear factor κB (NFκB) or the Ca⁺² calmodulin-dependent kinase (CaMK).