The role of ERK2 in germinal center B cell selection

Abstract

The regulation of B cell activation and survival is a crucial control point for the maintenance of B cell tolerance in the germinal center (GC) and involves the coordination of several intracellular signaling pathways. Dysregulation of these pathways can lead to the production and survival of autoreactive memory B cells and plasma cells (PCs), resulting in autoimmune disease. The mitogen-activated protein kinase (MAPK) pathway is involved in the transduction of stimulating and apoptotic signals such as those received through the B cell receptor (BCR) and the Fas receptor (CD95), respectively. Extracellular signal regulated kinases 1 and 2 (ERK1/2), important effectors of this pathway, play a major role in B cell activation and survival. Though ERK2 specifically regulates the pro-apoptotic protein, Bmf, its role in regulating GC B cell selection is unknown. Our lab has developed a novel mouse model in which the deletion of Erk2 is accompanied by the expression of the fluorescent reporter protein, eYFP, allowing us to identify and isolate viable Erk2Δ B cells using flow cytometry. Preliminary data using this model has shown that peripheral Erk2Δ B cells express several surface markers associated with follicular T helper cell interactions and immunoglobulin class switching, such as DEC205 and CD80, respectively. Thus we hypothesize that ERK2 is a critical regulator of GC B cell selection. We are currently investigating the ability of Erk2Δ B cells to respond to various activating stimuli in vitro as well as to differentiate into antigen-specific PCs. Our results will contribute to a better understanding of the molecular programs involved in B cell selection, potentially offering new approaches to treating B cell-driven autoimmune diseases.