Elucidating IKK1 function in germinal center B cell differentiation

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DESCRIPTION (provided by applicant): NF-kB signaling is regulated by the IkB kinase complex, consisting of IKK1, IKK2 and NEMO. However, recent studies have shown that IKK1 and IKK2 have largely distinct functions. In the proposed work, we will determine the intrinsic functions of IKK1 in GC B cells. We have recently reported that B cells expressing a mutant IKK1 molecule that cannot be phosphorylated by NIK (IKK1AA) do not form GCs. Herein we will determine the basis for this finding by examining IKK1- dependent functions in the GC via CD40/BAFF-R/TNF-R2 signaling and T cell costimulation. We will also assess activation of the IKK1 pathway in situ using immunohistochemical approaches. To complement these studies, mice will be generated expressing conditional IKK1flox/flox alleles to intercross with inducible B cell-specific Cre-expressing mice, thus allowing us to identify IKK1-dependent B cell functions prior to and during/after the GC reaction. These mice will be intercrossed with mice bearing mutant conditional IKK1 alleles to probe domain-specific functions of IKK1. Together, the proposed studies will provide definitive mechanistic insight into IKK1 function in vivo. PUBLIC HEALTH RELEVANCE: Germinal centers are microenvironments that form in the secondary lymphoid tissues following infection or immunization. It is here where B lymphocytes are selected to be high-affinity memory B cells or antibody-producing cells. Thus, understanding the molecular cues that guide germinal center B cell development is critical to understanding the basis of humoral immunity.