IL-27-producing B cells synergize with IFNγ to promote IgG2a and IgG1 antibody responses

How B cells integrate innate receptor and adaptive T cell signals in the class-switched antibody response needs be better understood. By using cytokine gene knockout and reporter mice, in vitro B cell cultures and single-cell analyses, we have identified a subset of B cells that produces IL-27 as signature cytokine upon priming by TLR ligands, which up-regulate CD40 expression, and exposure to Tfh cell stimuli CD154 and IL-21. B cell IL-27 induction depends on NF-kB activated by linear ubiquitin assembly complexes and up-regulated Baft3 transcription factor, which are recruited to the Il27p28 locus, as made accessible by CD154 and IL-21 stimulation. IL-27-producing B cells are bystander B cells that are inefficient in secreting antibodies, but express high levels of adhesion molecules which engage other activated B cells. Together with IFNg, they boost proliferation, survival and class-switching to IgG2a of B cells stimulated with CD154 and IL-21. Accordingly, mice with B cell-specific ablation of IL-27 and IFNg receptors display severe defects in germinal center B cell and plasma cell differentiation, leading to abrogation of IgG2a and markedly reduced IgG1 responses. Thus, IL-27-producing B cells function as “helper” cells to promote differentiation of antigen-specific B cells for optimal IgG responses. As such, they play a critical role in the production of effective anti-viral antibodies and, possibly, modulation of anti-tumoral immunity.