Novel Calcium Dependent Mechanisms of NF-kappaB Activation Regulate Lymphocyte Tolerance & Immunity
Thursday, May 31, 2018
2:00 PM-4:00 PM
BIOMED PhD Thesis Defense
Novel Calcium Dependent Mechanisms of NF-kappaB Activation Regulate Lymphocyte Tolerance and Immunity
Corbett T. Berry, MD/PhD Candidate, School of Biomedical Engineering, Science and Health Systems
Bruce D. Freedman, VMD, PhD, Associate Professor, School of Veterinary Medicine, University of Pennsylvania
Uri Hershberg, PhD, Associate Professor, School of Biomedical Engineering, Science and Health Systems, Drexel University
Antigen induced Ca2+ signals regulate the development of immunity and tolerance. These signals are generated when antigen binds cognate receptors on lymphocytes and triggers Ca2+ entry into the cytoplasm. Indeed, patients with functional defects in the ER transmembrane Ca2+-sensing STIM proteins, or the STIM-activated Ca2+ entry channel Orai, exhibit devastating immunodeficiency and autoimmunity.
This immune phenotype occurs as a result of dysfunctional lymphocyte development and function principally through aberrant activation of Ca2+ dependent transcription factors including NFAT and NF-kB. While the role of Ca2+ signaling in NFAT activation and signaling is well established, a wide appreciation and mechanistic understanding of how Ca2+ signals also shape the activation and specificity of NF-kB dependent gene expression is incomplete.
In these studies, we establish that STIM/Orai dependent Ca2+ entry regulates multiple checkpoints in NF-kB signaling, but also NF-kB independent pathways to regulate lymphocyte survival, proliferation, and differentiation.