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Novel calcium dependent mechanisms of NF-kappaB activation regulate lymphocyte tolerance and immunity
Dissertation   Open access

Novel calcium dependent mechanisms of NF-kappaB activation regulate lymphocyte tolerance and immunity

Corbett Timothy Berry
Doctor of Philosophy (Ph.D.), Drexel University
May 2018
DOI:
https://doi.org/10.17918/skhy-1y46
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Abstract

Calcium--Physiological effect Lymphocytes--Immunology Biomedical Engineering Immunology
The central role of calcium signaling in the development of functional immunity and tolerance is well established. These signals are initiated by antigen binding to cognate receptors on lymphocytes that trigger store operated calcium entry (SOCE). The underlying mechanism of SOCE in lymphocytes involves TCR and BCR mediated activation of Stromal Interaction Molecule 1 and 2 (STIM1/2) molecules embedded in the ER membrane leading to their activation of Orai channels in the plasma membrane. STIM/Orai dependent calcium signals guide key antigen induced lymphocyte development and function principally through direct regulation of calcium dependent transcription factors. The role of calcium signaling in NFAT activation and signaling is well known and has been studied extensively, but a wide appreciation and mechanistic understanding of how calcium signals also shape the activation and specificity of NF-kappaB dependent gene expression has lagged. Here we discuss and interpret what is known about calcium dependent mechanisms of NF-kappaB activation and extend these findings through a series of detailed experiments in T and B lymphocytes. We find that calcium plays a central role in NF-kappaB signaling in both human and mouse lymphocytes through regulation of the activation of the IKK complex, through post translational modification of NF-kappaB proteins, and through regulation of de novo NF-kappaB protein expression. We find that calcium signaling plays a central role in NF-kappaB dependent cell fates including lymphocyte survival, proliferation, and differentiation indicating that these mechanisms play a central role in the development of functional immunity and tolerance. We also define new mechanisms by which antigen receptor induced calcium signals regulate other key signaling pathways in lymphocytes including mTORC1 and shed light on the implications of these findings.

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