NFAT and NF-KB dynamically co-regulate TCR and CAR signaling responses in human T cells

While it has been established that the responses of T cells to antigens are combinatorially regulated by multiple signaling pathways, it remains elusive what mechanisms cells utilize to quantitatively modulate T cell responses during pathway integration. Here, we show that two key pathways in T cell signaling, calcium/nuclear factor of activated T cells (NFAT) and protein kinase C (PKC)/nuclear factor KB (NF-KB), integrate through a dynamic and combinatorial strategy to fine-tune T cell response genes. At the cis-regulatory level, the two pathways integrate through co-binding of NFAT and NF-KB to immune response genes. Pathway integration is further regulated temporally, where T cell receptor (TCR) and chimeric antigen receptor (CAR) activation signals modulate the temporal relationships between the nuclear localization dynamics of NFAT and NF-KB. Such physical and temporal integrations together contribute to distinct modes of expression modulation for genes. Thus, the temporal relationships between regulators can be modulated to affect their co-targets during immune responses, underscoring the importance of dynamic combinatorial regulation in cellular signaling.

Automated summary

The study reveals that T cell responses to antigens are regulated by multiple signaling pathways, and the mechanisms cells use to modulate T cell responses during pathway integration are still unclear. The calcium/NFAT and PKC/NF-KB pathways in T cell signaling integrate through a dynamic and combinatorial strategy to fine-tune T cell response genes. NFAT and NF-KB co-bind to immune response genes at the regulatory level, and the temporal relationships between the nuclear localization dynamics of NFAT and NF-KB are modulated by TCR and CAR activation signals. This physical and temporal integration contributes to distinct modes of expression modulation for genes.