The factors regulating germinal center (GC) B cell fate are poorly understood. Recent studies have defined a crucial role for the B cell–activating factor belonging to TNF family (BAFF; also called BLyS) in promoting primary B cell survival and development. A role for this cytokine in antigen-driven B cell responses has been suggested but current data in this regard are limited. A BAFF receptor expressed by B cells (BAFF-R/BR3) is defective in A/WySnJ mice which exhibit a phenotype similar to BAFF-deficient (BAFF−/−) animals. Here, we show that although GC responses can be efficiently induced in both A/WySnJ and BAFF−/− mice, these responses are not sustained. In BAFF−/− mice, this response is rapidly attenuated and accompanied by perturbed follicular dendritic cell development and immune complex trapping. In contrast, analysis of the A/WySnJ GC response revealed a B cell autonomous proliferative defect associated with reduced or undetectable Ki67 nuclear proliferation antigen expression by GC B cells at all stages of the response. These data demonstrate a multifaceted role for the BAFF pathway in regulating GC progression.

B cell–intrinsic IFN-γ receptor signaling through STAT1 is required for the generation of spontaneous germinal centers, which can lead to pathogenic autoantibody production.

Spontaneous germinal center (Spt-GC) B cells and follicular helper T cells (Tfh) generate high affinity autoantibodies involved in the development of systemic lupus erythematosus (SLE). Toll like receptors (TLRs) play a pivotal role in SLE pathogenesis. While previous studies have focused on the B cell intrinsic role of TLR-MyD88 signaling on immune activation, autoantibody repertoire and systemic inflammation, a thorough investigation of the mechanisms by which TLRs control the formation of Spt-GCs remains unclear. Using non-autoimmune C57BL/6 (B6) mice deficient in MyD88, TLR2, 3, 4, 7 or 9, we identified B cell-intrinsic TLR7 signaling as a prerequisite to Spt-GC formation without the confounding effects of autoimmune susceptibility genes and the overexpression of TLRs. TLR7 deficiency also rendered autoimmune B6.Sle1b mice unable to form Spt-GCs, leading to markedly decreased autoantibodies. Conversely, B6.yaa and B6.Sle1b.yaa mice expressing an extra copy of TLR7 and B6.Sle1b mice treated with a TLR7 agonist had increased Spt-GCs and Tfh. Further, TLR7/ MyD88 deficiency led to compromised B cell proliferation and survival after B cell stimulation both in vitro and in vivo. In contrast, TLR9 inhibited Spt-GC development. Our findings demonstrate an absolute requirement of TLR7 and a negative regulatory function for TLR9 in Spt-GC formation under non-autoimmune and autoimmune conditions. Our data suggest that, under non-autoimmune conditions, Spt-GCs initiated by TLR7 produce protective antibodies. However, in the presence of autoimmune susceptibility genes, TLR7 dependent Spt-GCs produce pathogenic autoantibodies. Thus, a single copy of TLR7 in B cells is the minimal requirement for breaking the GC-tolerance checkpoint.