This application is submitted in response to the Notice Number (NOT-OD-09-058): NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The overall objective of this Competitive Revision (CR) application is to examine the signaling mechanism by which the NF- kB-inducing kinase (NIK) regulates Th17 cell differentiation and EAE induction. Th17 cells are a subset of CD4 effector T cells critically involved in autoimmune diseases, particularly experimental autoimmune encephalomyelitis (EAE). Since EAE is an animal model of human multiple sclerosis (MS), elucidation of the molecular mechanism of EAE pathogenesis is important for rational design of MS therapies. The studies proposed in this CR application are based on our novel finding that NIK has a pivotal role in regulating Th17 cell differentiation and EAE induction. NIK is a kinase known to mediate activation of noncanonical NF-kB signaling, which involves phosphorylation and proteasomal processing of the NF-kB2 precursor protein, p100, and nuclear translocation of the p52/RelB NF-kB complex. Although NIK is known for its role in regulating B-cell maturation and lymphoid organ development, how NIK regulates T-cell effector function is poorly understood. Our finding that NIK regulates Th17 cell differentiation and EAE induction uncovers a novel and important function of NIK. Thus, the studies proposed in this CR application are both significant and innovative. We have shown that NIK-deficient naive CD4 T cells are attenuated in Th17 cell differentiation, although they are competent in differentiating to other subsets of effector T cells. We have further demonstrated that NIK has a T-cell intrinsic function in regulating Th17 differentiation and EAE induction. Interestingly, our studies identified a novel signaling function of NIK, which involves activation of a key Th17-regulatory transcription factor, STAT3. NIK mediates synergistic activation of STAT3 by the T-cell receptor and IL-6 receptor signals. Since STAT3 is known to physically interact with and functionally cooperate with NF-kB proteins, we hypothesize that NIK may regulate Th17 differentiation and EAE pathogenesis by mediating activation of both noncanonical NF-kB and STAT3. We will (1) determine the mechanism and functional significance of NIK-mediated STAT3 activation in CD4 T cells, (2) examine the role of noncanonical NF-kB in the regulation of Th17 differentiation and EAE pathogenesis, (3) examine the role of TRAF3 in NIK regulation and Th17 cell differentiation, and (4) define the domains/motifs of NIK that are required for its Th17-regulatory function.
Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) that involves pathological actions of inflammatory T cells. Understanding the molecular mechanism of EAE pathogenesis is very important for rational design of MS therapies. The goal of this revision project is to understand the molecular mechanism by which a protein kinase, NIK, regulates inflammatory T-cell production and EAE pathogenesis.
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