Background The B cell survival cytokine BAFF has been linked with the pathogenesis of SLE. BAFF binds distinct B cell surface receptors, including the BAFF receptor (BAFF-R) and Transmembrane Activator and CAML Interactor (TACI). Although originally characterized as a negative regulator of B cell activation, TACI signals are critical for class-switched autoantibody production in BAFF transgenic (Tg) mice. Notably, while surface TACI expression is usually limited to mature B cells, we showed that excess BAFF promotes the expansion of TACI-expressing transitional B cells, with these cells representing an important source for class-switched autoantibodies in BAFF-Tg mice (Jacobs, et al. J Immunol, 2016). In the current study, we interrogate the signals required for transitional B cell TACI expression and BAFF-driven autoantibody production.
Methods We first used a new ‘fate-mapping’ strategy to confirm that activated TACI+ B cells falling within CD21lo transitional flow cytometry gates are bone fide transitional B cells. Subsequently, we interrogated the B cell signals required for transitional B cell TACI expression and antibody production using relevant murine genetic models crossed on the BAFF-Tg background.
Results To confirm that immature, transitional B cells are a prominant source for class-switched autoantibodies in BAFF-Tg mice, we developed a CD21Cre.ROSA-YFPfl/fl reporter strategy. By irreversibly labeling B cells that have expressed CD21, we confirmed that transitional B cells that had not yet differentiated beyond the T2 stage spontaneously produce class-switched autoantibodies in BAFF-Tg animals. We next determined the signals required for TACI upregulation on T1 transitional B cells. Surprisingly, signals downstream of B cell (BCR) and Toll-like (TLR) receptors exerted distinct impacts on transitional B cells. Whereas loss of BCR signals in Btk-/- .BAFF-Tg mice prevented transitional B cell TACI expression and resulted in loss of serum autoantibodies across immunoglobulin isotypes, lack of Myd88/TLR7 signals exerted a limited impact on autoantibody class switch recombination without impacting transitional B cell TACI expression. Moreover, in parallel with the protective effect of TACI deletion, loss of BAFF-R activation signals protected against BAFF-driven autoimmunity. Notably, integration of all these signalling cascades (BCR, TACI, TLR7/MyD88, and BAFF-R) is required for production of pathogenic class-switched autoantibodies in BAFF-Tg mice, and for development of BAFF-driven lupus nephritis.
Conclusions In summary, we highlight how distinct signaling pathways integrate to promote class-switched autoantibody production by transitional B cells, findings with implications to the understanding of SLE pathogenesis and other humoral autoimmune diseases characterized by elevated serum BAFF.
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