Regulation of innate and adaptive immune responses through toll-like receptor activation.

摘要

The vertebrate immune system is a coordinated interplay between the innate and adaptive immune systems, former of which forms the first line of defense against invading pathogens. Sets of evolutionarily-conserved receptors, such as the Toll-like receptor (TLR) family members, recognize microbial products to activate differential signal transduction cascades resulting in the induction of specialized antibacterial or antiviral responses. Type I interferon (IFN) production is a critical component of the innate antiviral response. In the first part of our studies, we have studied the role of TRAF3, a member of the TNF receptor associated factor family, in the generation of antiviral responses upon TLR activation or viral infection. Our studies demonstrate that cells lacking TRAF3 are defective in the type I IFN induction by TLRs 3, 4, 7, and 9. We further show that TRAF3 associates with the TLR adapters TRIF and MyD88, as well as downstream IRF3/7 kinases TBK1 and IKKepsilon, suggesting that TRAF3 serves as a critical link between TLR adapters and downstream regulatory kinases important for IRF3/7 activation. Finally, TRAF3-deficient cells were not only defective in TLR-mediated type I IFN production and subsequent viral inhibition but also defective in type I IFN induction upon direct viral infection, implicating TRAF3 in the intracellular viral recognition pathway. In support of this, we showed that TRAF3 associates with a putative intracellular viral recognition protein PKR. Together, these studies suggest that TRAF3 is a master regulator of type I IFN production by both TLR activation and viral infection.;In addition to activating immediate defense mechanisms, TLR agonists also serve as potent adjuvants for enhancing the adaptive immune responses. Interestingly, certain TLR agonists, such as CpG DNA, can not only serve as adjuvants but may also play a critical role in the development of autoimmune disease such as Systemic Lupus Erythematosus (SLE). In our studies we demonstrate that, in addition to dendritic cells (DCs), murine B lymphocytes respond to CpG DNA to produce type I interferons (IFNs). Unlike DCs, B cell activation of type I IFNs at least partly requires IRF3. Furthermore, CpG-mediated type I IFN production by B cells enhanced Syndecan-1 expression and IgM secretion and was required for IgG2a production. These findings suggest that type I IFNs play a central role in mediating B cell biology in response to CpG, potentially implicating this pathway in the production of pathogenic IgG2a in autoimmune disease.