Advisory Committee Chair
Etty N Benveniste
Advisory Committee Members
Charles O Elson
Laurie E Harrington
Michael A Miller
Hongwei Qin
Chander Raman
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Protein kinase CK2 is a highly conserved serine/threonine kinase essential for cell viability. CK2 exhibits immense pleiotropy and has well characterized interactions with canonical cytosolic signaling pathways such as PI3K/Akt/mTOR and JAK/STAT. These pathways are critical for CD4+ T cell function, and further are known to be aberrantly active in the T cell-driven autoimmune disease Multiple Sclerosis, but little is known as to how CK2 functions in CD4+ T cells or in the context of autoimmune diseases. The current dissertation examines the understudied T cell-specific functions of CK2 utilizing two approaches, pharmacologic inhibition and genetic deletion. We discovered CK2 to be robustly induced upon CD4+ T cell activation, but to be largely dispensable for the expression of activation-induced surface markers and proliferation. Rather, CK2 played a critical role in regulating CD4+ T cell differentiation. Targeting CK2 activity specifically and significantly inhibited Th17 cell differentiation. In addition, decreased Th17 cell differentiation was accompanied by a reciprocal robust increase in the generation Foxp3+ Tregs in vitro and in the context of autoimmune neuroinflammation. The regulation of the Th17/Treg axis by CK2 was associated with Akt/mTOR, and STAT3 signaling, and was dependent on the activity of Treg-promoting transcription factor FoxO1. Furthermore, targeting CK2 significantly inhibited the capacity of Th17 cells to produce IFN-γ in vitro and the generation of pathogenic IFN-γ and/or GM-CSF co-producing Th17 during T cell-driven neuroinflammation. Overall, we demonstrate several novel features of CK2 activity in the context of CD4+ T cells, and identify CK2 as a potential target for Th17 cell-driven autoimmune disorders. Furthermore, our data have implications for numerous disorders in with the Th17/Treg axis and Th17 cell maturation play a modulatory role.
Recommended Citation
Gibson, Sara Ann, "The Function of Protein Kinase CK2 in CD4 T Cell Differentiation and Autoimmunity" (2017). All ETDs from UAB. 1739.
https://digitalcommons.library.uab.edu/etd-collection/1739
