Coordinated Regulation of Extrafollicular B Cell Responses by IL-12 and IFNγ

Abstract

Upon activation, B cells undergo either the germinal center (GC) or extrafollicular (EF) response. While GC are known to generate high-affinity memory B cells and long-lived plasma cells, the role of the EF response is less well understood. Initially, it was thought to be limited to that of a source of fast but lower-quality antibodies until the GC can form. However, recent evidence strongly supports the EF response as an important component of the humoral response to infection. EF responses are now also recognized as a source of pathogenic B cells in autoimmune diseases. The EF response itself is dynamic and regulated by pathways that are only recently being uncovered. We have identified that the cytokine IL-12 acts as a molecular switch, enhancing the EF response and suppressing GC through multiple mechanisms. These include direct effects on both B cells themselves and the coordinated differentiation of helper CD4 T cells. Here, we explore this pathway in relation to other recent advancements in our understanding of the EF response's role and highlight areas for future research. A better understanding of how the EF response forms and is regulated is essential for advancing treatments for many disease states.

Keywords: B cell; IL‐12; autoimmunity; extrafollicular; germinal center; infection.

FIGURE 1

Proposed model of IL‐12 and IFNγ signaling in B cells. IFNγ upregulates the expression of suppressor of cytokine signaling family members (SOCS1, SOCS3, CISH). In the absence of other signals, high concentrations of IFNγ are necessary to overcome inhibition. When IL‐12 is present, IL‐12 upregulates IFNγ production. IFNγ induces the secretion of some IL‐12 that is not transcriptionally regulated and transcriptionally promotes the expression of STAT4 and the IL‐12Rβ1 subunit of the IL‐12 receptor. Additionally, combined signals from IL‐12 and IFNγ upregulate STAT1 and the IL‐12Rβ2 subunit. IL‐12 signaling enhances IFNγ production in a dose‐dependent way, establishing a positive feedback loop between IL‐12 and IFNγ. Hypothetically, the combined signals overcome IFNγ‐induced negative regulation, ultimately promoting PC differentiation.

FIGURE 2

Schematic of putative transcription factor networks in IL‐12 and IFNγ‐stimulated B cells. Initially upon stimulation with IL‐12, B cells produce IFNγ which in turn induces the expression of T‐bet and IRF1. In CD4 T cells, IRF1 promotes IL‐12Rβ1 subunit expression, and T‐bet enhances IL‐12Rβ2 and STAT4 indirectly through repression of GATA3. IFNγ also induces the secretion of IL‐12, the mechanism for this is unclear, but could involve BATF2 or IRF8. The signaling network evolves over time, leading to enhanced expression of some genes, and synergistic upregulation of a portion of other genes including BATF2 and IRF8 (purple). IFNγ also promotes the expression of Blimp‐1 and an inflammatory gene program including NF‐κB. T‐bet indirectly enhances plasma cell differentiation in part by antagonizing NF‐κB. Over time, the positive feedback loop and/or synergistic regulation culminates in enhanced IRF4 expression, which promotes PC differentiation. Many of these proposed connections are based on the transcription factor activities during T_H1 differentiation, and it remains to be seen whether they function similarly in B cells.