IFN- amplifies human naı̈ve B cell TLR-9- mediated activation and Ig production

TLRs are a family of molecules that function as sensors for the detection of pathogens. TLR-9, expressed on B cells and pDCs, recognizes CpG motifs of unmethylated bacterial DNA and plays a role in the development of autoimmunity. The present study was designed to investigate the effects of IFNin combination with CpG ODN on the activation of CD27 naı̈ve B cells and on Ig production. We provide evidence that CpG ODN not only induces a total and T-dependent, specific IgM response by naı̈ve B cells but also their phenotypic differentiation in plasma cells, as demonstrated by the upregulation of CD38 expression. We found that TLR-9 stimulation with CpG ODN induces IL-1 , TNF, IL-10, and IL-6 production. Interestingly, we also found that CpG ODN induces naı̈ve B cell maturation into memory cells, as demonstrated by the induction of CD27, AID mRNA expression, and IgG production. More importantly, our results demonstrate that IFNamplifies the inductive effect of CpG ODN on naı̈ve B activation and on Ig production through a mechanism involving TLR-9/ MyD88-dependent signaling. Moreover, we found that IFNenhances the frequency of CpG ODN-induced memory B cells. Our results may contribute to clarify the events promoting IFN-induced amplification of naı̈ve B cell activation via TLR-9 for a better understanding of the pathogenesis of autoimmune disorders and may guide treatments targeting this pathway within B cells. J. Leukoc. Biol. 86: 000–000; 2009.