The calcium/NFAT pathway: role in development and function of regulatory T cells

Abstract

Calcium signals are essential for diverse cellular functions in the immune system. Sustained Ca(2+) entry is necessary for complete and long-lasting activation of calcineurin/NFAT pathways. A growing number of studies have emphasized that Ca(2+)/calcineurin/NFAT pathway is crucial for both development and function of regulatory T cells.

Figure 1

Store-operated Ca²⁺ entry in T cells. The binding of antigen/MHC complexes to the 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 Ca²⁺ concentration and activates the calcineurin-NFAT pathway as well as regulating the CaMK-CREB pathway.

Figure 2

Transcriptional regulation of the development and function of regulatory T cells. A). NFAT binds both promoter and enhancer regions of Foxp3 gene[54, 57, 61, 62]. B). Crystal structure of NFAT - Foxp on IL-2 promoter. NFAT cooperates with Foxp3 to suppress IL-2 production[58]. Abbreviation: ARRE, antigen-receptor response element which also binds NFAT-Fos-Jun complexes in conventional activated T cells.