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

Area of Science:

• Immunology
• Cellular Signaling
• Molecular Biology

Background:

• T cell responses to antigens are regulated by multiple signaling pathways.
• Mechanisms for quantitative modulation of T cell responses during pathway integration are not fully understood.

Purpose of the Study:

• To investigate how T cells quantitatively modulate responses through integration of key signaling pathways.
• To elucidate the mechanisms of dynamic and combinatorial regulation in T cell signaling.

Main Methods:

• Analysis of cis-regulatory elements and transcription factor co-binding (NFAT and NF-κB).
• Investigation of temporal dynamics of nuclear localization of NFAT and NF-κB following T cell receptor (TCR) and chimeric antigen receptor (CAR) activation.
• Studying gene expression modulation through physical and temporal integration of signaling pathways.

Main Results:

• Two key T cell signaling pathways, calcium/NFAT and PKC/NF-κB, integrate via a dynamic, combinatorial strategy.
• Integration occurs at the cis-regulatory level through co-binding of NFAT and NF-κB to immune response genes.
• TCR and CAR activation signals modulate the temporal relationship between NFAT and NF-κB nuclear localization, impacting gene expression.

Conclusions:

• Dynamic and combinatorial integration of signaling pathways fine-tunes T cell responses.
• Temporal relationships between regulators are crucial for modulating co-target genes during immune responses.
• This study highlights the importance of dynamic combinatorial regulation in cellular signaling for immune responses.