Calcium signaling in lymphocytes

Abstract

In cells of the immune system, calcium signals are essential for diverse cellular functions including differentiation, effector function, and gene transcription. After the engagement of immunoreceptors such as T-cell and B-cell antigen receptors and the Fc receptors on mast cells and NK cells, the intracellular concentration of calcium ions is increased through the sequential operation of two interdependent processes: depletion of endoplasmic reticulum Ca(2+) stores as a result of binding of inositol trisphosphate (IP(3)) to IP(3) receptors, followed by 'store-operated' Ca(2+) entry through plasma membrane Ca(2+) channels. In lymphocytes, mast cells and other immune cell types, store-operated Ca(2+) entry through specialized Ca(2+) release-activated calcium (CRAC) channels constitutes the major pathway of intracellular Ca(2+) increase. A recent breakthrough in our understanding of CRAC channel function is the identification of stromal interaction molecule (STIM) and ORAI, two essential regulators of CRAC channel function. This review focuses on the signaling pathways upstream and downstream of Ca(2+) influx (the STIM/ORAI and calcineurin/NFAT pathways, respectively).

Figure 1

Store-operated Ca²⁺ entry in T cells. The binding of antigen/MHC complexes to T cell receptor (TCR) triggers the activation of protein tyrosine kinases, such as LCK and ZAP70, which eventually results in tyrosine phosphorylation and activation of PLC-γ1. PLC-γ1 hydrolyzes the membrane phospholipid PIP₂ to IP₃ and DAG. IP₃ opens IP₃ receptors (IP₃R), which permits Ca²⁺ efflux from ER Ca²⁺ stores. The ER Ca²⁺ sensors STIM1 and STIM2 sense the resulting reduction of ER Ca²⁺ stores via their paired N-terminal EF-hands located in the ER lumen. After Ca²⁺ dissociates from the EF-hands, STIM proteins aggregate into small clusters (“puncta”) in the ER membrane and trigger store-operated Ca²⁺ entry via the CRAC channel, ORAI1. Ca²⁺ influx elevates intracellular Ca concentration and activates the calcineurin-NFAT pathway as well as regulates the Ras-MAPK pathway.

Figure 2

T cell development in thymus. CD4⁺ CD8⁺ double positive (DP) thymocytes differentiate into conventional CD4⁺ or CD8⁺ single positive (SP) αβTCR⁺ thymocytes, or CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells (T_reg cells). STIM-dependent store-operated Ca²⁺ entry appears to be crucial for the development of T_reg cells but dispensable for the development of conventional αβTCR⁺ thymocytes[••45]. We speculate that other Ca²⁺ entry pathways might compensate for loss of STIM-dependent store-operated Ca²⁺ entry in the differentiation of DP thymocytes into conventional αβTCR⁺ SP thymocytes.