Figure 1. (Graphical Abstract): Antigen receptor induced Ca²⁺ dynamics tune the patterns. of transcriptional activation.

This schematic proposes how variations in antigen receptor induced Ca²⁺ dynamics elicit distinct patterns of gene expression depicted by a heatmap of differential gene expression. Work over the past 30 years has established that the strength of antigen receptor stimulation is encoded as quantitatively distinct patterns of Ca²⁺ signaling, and that these can each initiate a distinct transcriptionally driven fate of lymphocytes by activating Ca²⁺ dependent transcription factors. The key pro-inflammatory transcription factors NF-κB and NFAT, which exhibit differences in Ca²⁺ sensitive activation, decode differences in the strength of antigen stimulation into distinct patterns of transcriptional activation. High affinity antigen binding causes sustained STIM/Orai-dependent Ca²⁺ entry and these signals activate both NF-κB and NFAT. Intermediate antigen affinity/avidity interactions cause distinct patterns of signaling, possibly Ca²⁺ oscillations, that preferentially activate NF-κB and depending on the frequency can potentially activate NFAT. Low affinity/avidity interactions that cause a significant but transient elevation in cytoplasmic Ca²⁺ leading to the selective activation of NF-κB signaling and NF-κB dependent target gene expression. Finally, in the absence of Ca²⁺ entry, low amplitude, transient elevations in cytoplasmic Ca²⁺ may be insufficient for the activation of either NF-κB or NFAT.