Immunodeficiency Is A Tough Nut to CRAC: The Importance of Calcium Flux in T Cell Activation

Calcium is essential for the effector processes that occur downstream of T cell receptor activation. T cells recognize antigen in the form of a peptide fragment presented in the context of MHC via the TCR/CD3 complex on the cell surface. (TCR appears as two dark red ovals; CD3 complex appears as three green ovals adjacent to TCR.) Activation results in the phosphorylation of PLC-γ1, leading to the hydrolysis of PIP₂, generating DAG and IP₃. IP₃ causes the release of calcium from stores within the endoplasmic reticulum which is detected by STIM1. This causes the opening of CRAC channels in the plasma membrane and Ca²⁺ influx leading to NFAT activation, via calmodulin and calreticulin, and the transcription of genes responsible for T cell effector function (i.e., IL-2). TCR, T cell antigen receptor; MHC, major histocompatability complex; PLC-γ1; phospholipase C–γ1; PIP₂, phosphatidylinositol bisphosphate; DAG, diacylglycerol; IP₃, inositol-3,4,5-trisphosphate; IP₃R, inositol trisphosphate receptor; ER, endoplasmic reticulum; NFAT, nuclear factor of activated T cells; CRAC, Ca²⁺-release-activated Ca²⁺channel; IL-2, interleukin-2.