All ETDs from UAB

Advisory Committee Chair

Chander Raman

Advisory Committee Members

Etty Benveniste

Janusz Kabarowski

Robin Lorenz

Casey Weaver

Allan Zajac

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

CD5 is expressed on T and B1a cells and is an important regulator of cell survival and activation. Engagement of CD5 promotes cell survival through the activation of the serine threonine kinase CK2. Mice with genetic abrogation of CD5 binding to CK2 (CD5∆CK2bd) exhibited reduced severity of experimental autoimmune encephalomyelitis that was associated with increased activation induced cell death. In addition to inhibiting cell death, CD5 activation of CK2 significantly enhances Th17 differentiation. Loss of CD5-CK2 signaling reduces the generation of Th17 cells despite an unexpected increase in pSTAT3 levels. The mechanisms of CD5's enhancement of Th17 differentiation have not been previously described. I have determined that CD5-CK2 signaling enhances Th17 differentiation through activation of the AKT signaling pathway. CD5 activation of AKT increases nuclear levels of RORγt and further augments Th17 differentiation by inhibiting GSK3. Pharmacological inhibition of GSK3 significantly enhances Th17 differentiation within the first three days of stimulation. Furthermore, GSK3 is necessary for optimal IFN-γR signaling in T cells and inhibition of GSK3 by CD5 dampens IFN-γ inhibition of Th17 differentiation. I sought to determine if CD5-CK2 signaling affected other cytokine receptors. Because, the IL-6 receptor requires CK2 activity for STAT activation we hypothesized that CD5 could enhance IL-6 signaling. Surprisingly, CD5 does not alter IL-6R signaling, but CD5 was found to be a potent enhancer of IL-10R signaling. I determined that the IL-10R also requires active CK2 for STAT3 activation. CD5-CK2 signaling augments IL-10 inhibition of IL-2 secretion and increases expression of SOCS3. These results greatly broaden our understanding of the function of CD5. In addition to cell survival, CD5 enhances Th17 differentiation by enhancing nuclear translocation of RORγt and by inhibiting IFN-γR signaling. The IL-10R signaling is also enhanced by CD5 activation of CK2.

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