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Mobilizing ER IP3 receptors as a mechanism to enhance calcium signaling

Cellular & Molecular Immunology volume 18, pages 2284–2285 (2021)Cite this article

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Calcium is an important cell signaling intermediate known to play a critical role in T-cell receptor (TCR)-mediated activation of both developing thymocytes and mature peripheral T cells. Upon antigen engagement, the TCR recruits PLCγ1 to the proximal signaling complex to be phosphorylated and activated by the membrane-bound kinase Itk. Activated PLCγ1 mediates the cleavage of the cell membrane lipid component PIP2 into the lipids diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). IP3 is diffusible within the cytosol and binds its receptors (IP3Rs) on the ER membrane to trigger the release of stored calcium from the ER lumen into the cytosol. Increased cytosolic calcium, in turn, triggers cluster formation by the calcium-binding transmembrane protein STIM1, which then pairs with calcium release-activated calcium channels (CRACs) on the plasma membrane. This induces the opening of CRACs on the plasma membrane to initiate calcium flux from outside of the cell. Increased cytosolic calcium flux induces the activation of calcium/calmodulin-dependent kinases and the phosphatase calcineurin. Calcineurin dephosphorylates and activates nuclear factor of activated T cells (NFAT), one of the most critical transcription factors in T cells, and triggers the gene expression programs responsible for cell survival, proliferation, and effector functions [1].

It has been well acknowledged that TCR signaling outcomes differ significantly between developing thymocytes and mature T cells. DP thymocytes (termed preselection DPs) are highly sensitive to low-affinity ligands, and during low-affinity ligand binding, a weaker signal is essential to promote cell survival. This phenomenon allows for positive selection of developing thymocytes by low-affinity cross-reactive self-peptides. However, TCR sensitivity is dramatically downregulated in post-selection mature T cells, which is considered helpful to prevent mature T cells from responding inappropriately to self-antigens [2]. However, the reason behind this difference remains elusive.

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Fig. 1: Mobilizing ER IP3Rs as a mechanism to facilitate calcium signaling: Several IP3R binding proteins, including Tespa1, BANK1, and SLAT, have been found in T and B cells.

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Authors and Affiliations

  1. Institute of Immunology, and Department of Rheumatology in Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China

    Linrong Lu

  2. Zhejiang University-University of Edinburgh Institute, Zhejiang University School of Medicine, Haining, P. R. China

    Linrong Lu

  3. Dr. Li Dak Sum and Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, P. R. China

    Linrong Lu

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Lu, L. Mobilizing ER IP3 receptors as a mechanism to enhance calcium signaling. Cell Mol Immunol 18, 2284–2285 (2021). https://doi.org/10.1038/s41423-021-00725-5

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