TRAF3-EWSR1 signaling axis acts as a checkpoint on germinal center responses

The formation of germinal centers (GCs) is crucial for humoral immunity and vaccine efficacy. Constant stimulation through microbiota drives the formation of constitutive GCs in Peyer's patches (PPs), which generate B cells that produce antibodies against gut antigens derived from commensal bacteria and infectious pathogens. However, the molecular mechanism that regulates this persistent process is poorly understood. We report that Ewing Sarcoma Breakpoint Region 1 (EWSR1) is a brake to constitutive GC generation and immunoglobulin G (IgG) production in PPs, vaccination-induced GC formation, and IgG responses. Mechanistically, EWSR1 suppresses Bcl6 upregulation after antigen encounter, thereby negatively regulating induced GC B cell generation and IgG production. We further showed that tumor necrosis factor receptor-associated factor (TRAF) 3 serves as a negative regulator of EWSR1. These results established that the TRAF3-EWSR1 signaling axis acts as a checkpoint for Bcl6 expression and GC responses, indicating that this axis is a therapeutic target to tune GC responses and humoral immunity in infectious diseases. Li et al. reveal that the TRAF3-EWSR1 signaling axis serves as a critical checkpoint in the regulation of induced germinal center (GC) responses and immunoglobulin production. This signaling axis acts as a negative regulator of Bcl6 upregulation, which in turn negatively affects GC B cell generation and IgG production.

Automated summary

Li et al. demonstrate that the TRAF3-EWSR1 signaling axis functions as a critical checkpoint in regulating induced germinal center (GC) responses and immunoglobulin production. This signaling axis acts as a negative regulator of Bcl6 upregulation, thus negatively impacting GC B cell generation and IgG production.