Antibodies are generated through two distinct pathways following B cell activation: the rapid generation of short-lived antibody-secreting plasma blasts and plasma cells (so called extrafollicular responses, EFRs) and the slower development of germinal center reactions (GCs). During the latter, B cells undergo clonal expansion, diversification and affinity maturation, and the generation of long-lived plasma cells as well as memory B cells that often respond to a repeat challenge with EFRs. The mechanisms regulating the differentiation of B cells along one or the other response type are incompletely understood, but critical for understanding how to intervene in ineffective or harmful humoral responses. Using a mouse model of influenza infection we demonstrate that the development of EFRs is dependent on B cell intrinsic and extrinsic, inflammatory, Toll-like receptor (TLR) signals. B cell-intrinsic TLR signals supported antigen-stimulated B cell survival, clonal expansion, and the differentiation of B cells via induction of IRF4, the master regulator of B cell differentiation, through activation of NF-kB c- Rel. Provision of sustained TLR4 stimulation after immunization altered the fate of virus-specific B cells towards EFRs instead of GCs. Thus, acute inflammatory signals enhance antibody production as a means to provide rapidly protective antibodies in infections. During chronic inflammation, the same signals may drive a continued and potentially harmful autoantibody response, indicating that control of inflammation may curb pathogenic antibody responses.
Work was supported by NIH R01AI148652
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