The role of ERK2 in regulating germinal center B cell fate decisions

Abstract

Abstract The regulation of B cell activation, differentiation, and survival is a crucial control point for the maintenance of B cell tolerance in the germinal center (GC) and involves the precise coordination of several complex intracellular signaling pathways. Dysregulation of these pathways can lead to the generation and persistence of autoreactive memory B cells and antibody-secreting cells (ASCs), resulting in autoimmune disease. The mitogen-activated protein kinase (MAPK) pathway is central to signals required for GC B cell selection and differentiation, such as those received through the B cell receptor (BCR) and C-X-C chemokine receptor type 4 (CXCR4), respectively. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), important effectors of this pathway, play a major role in B cell activation and differentiation. Though ERK2 specifically regulates the pro-apoptotic protein, Bmf, its role in regulating GC B cell fate is unknown. Our lab has developed a 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 DEC205, which is associated with follicular T helper cell interactions and CD80, which is involved in co-stimulation and immunoglobulin class switching. Thus, we hypothesize that ERK2 regulates several aspects of GC B cell selection. Our results will help elucidate the molecular mechanisms underlying B cell differentiation, potentially offering new approaches to treating B cell-driven autoimmune diseases.