Delineation of the signaling mechanisms that guide the differentiation and selection of germinal center B cells remains a challenging topic. From a genetic approach, the ability to selectively modify genes in germinal center B cells has only recently been achieved. Moreover, germinal center B cells represent a small and transient subset of B cells that are difficult to maintain or expand in vitro. Nonetheless, it is imperative o develop new approaches to study this subset as it is becoming clear that activation and differentiation characteristics of more abundant nave recirculating B cells are not representativ of the heterogeneous germinal center B cell compartment. Herein we will focus on the NIK/IKK1 axis, which we have found to be required for germinal center formation, but the downstream functional targets are unidentified. Here we will utilize cutting edge mass cytometry, imaging cytometry, specialized in vitro cultures and conditional gene targeting to dissect the individual and combined roles of NIK and IKK1 in germinal center B cell differentiation. These studies will provide novel insights into the signal transduction pathways accounting for the generation of high-affinity memory B cells and plasma cells, as well as a better understanding of how dysregulation of NIK/IKK1 signaling promotes multiple myeloma and lymphomagenesis
The proposed studies will provide fundamental insight into the mechanisms that govern the germinal center B cell response, which accounts for the generation of high-affinity memory B cells and antibody-producing cells. In addition, they will inform on how dysregulated NIK/IKK1 activity contributes to myeloma and lymphoma.
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