Distinct Molecular Mechanisms Receptor Regulate TLR7 Responses via Type I IFN Receptor and the B Cell Antigen

Toll-like receptor 7 (TLR7) signals to B cells are critically involved in the innate immune response to microbes, as well as path-ogenesis of autoimmune diseases, but the molecular mechanisms that normally regulate these responses are incompletely understood. We previously reported that repeated stimulation through TLR7 induces a state of hyporesponsiveness (TLR tolerance) in both human and mouse B cells, characterized by marked inhibition of particular signaling pathways. BCR signals prevent and overcome TLR7 tolerance. Because optimal responses to TLR7 in B cells require type I IFN, we investigated whether BCR-mediated effects on TLR7 tolerance are mediated by type I IFN receptor (IFNAR) signals. Surprisingly, although BCR-mediated reversal of TLR7 tolerance was IFNAR independent, IFNAR signals alone also blocked TLR7 tolerance, despite enhancing TLR7 expression. Both BCR and IFNAR signals restored the phosphorylation of the transcriptional regulator c-Jun, but only BCR signals blocked the tolerance-mediated inhibition of JNK. Both BCR and IFNAR-mediated regulation was dependent on activation of the PI3K/Akt/mammalian target of rapamycin signaling pathway, indicating a central role for this axis in integrating TLR7, BCR, and IFNAR signals in B cells. These new findings reveal distinct and overlapping signaling mechanisms used by BCR and IFNAR in the regulation of TLR7 tolerance and activation. W ell-coordinated and tightly regulated signaling through innate and adaptive immune receptors is central to the development of an effective immune response, but dysregulated signaling can lead to excessive inflammation and immunopathology (1, 2). Pattern recognition receptors, including those belonging to the TLR family, are key players in the initiation of innate immune responses (3). TLR-expressing cells of the myeloid lineage, including dendritic cells (DCs) and macro-phages, play central roles in innate immunity. However, B cells, the only cell type capable of producing Ab, also express a variety of TLRs (4). B cells produce key inflammatory cytokines such as TNF-a and IL-6 in response to TLRs, and are especially responsive to TLR7 and TLR9 (5-7). TLR stimulation also promotes Ig class-switch recombination and Ab secretion (8). Both Ab-dependent and-independent TLR-stimulated B cell functions play crucial roles in protection against infectious pathogens (9). TLR signals also interact with signals delivered through a variety of B cell surface receptors. TLR7 signals synergize with BCR and CD40 signals to promote B cell Ag presentation, via upregulation of costimulatory molecules and cytokine production (10). Recent studies reveal a critical role for type I IFN receptor (IFNAR) signals in regulating TLR-mediated B …