Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses

Hideo Negishi et al. Nat Immunol. (2012). 13(7):659-66.

Speaker: Mei-Ling Lai (賴玫伶)                                   Time: 14:00~15:00, Dec 7, 2012

Commentator: Dr. Lien-I Hor (何漣漪 博士)             Place: Room 601

Abstract

        Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and RIG-I–like receptors, recognize distinct microbial components and directly activate immune cells. Although these interactions can augment the overall immune response, little is known about the extent to which these pathways interfere with each other or about the mechanisms of such interference. The authors found that virus-induced activation of RLRs resulted in selective suppression of the bacteria- and TLR-induced gene Il12b, which encodes the p40 subunit of both interleukin 12 (IL-12) and IL-23 (IL-12p40). The effect of the RLR signaling is explained by IRF3. IRF3 activated by the RLRs is also recruited to the Il12b promoter and suppresses its transcription induced by stimulation of TLRs, at least in part by inhibiting recruitment of IRF5 to the promoter region. The recruitment of IRF5 is suppressed by the RLRs and is restored by the absence of IRF3. IL-12 and IL-23 are produced by DCs and macrophages, are responsible for the polarization of helper T cells into the following distinct subsets: T_H1 and T_H17¹. The authors found that treatment of mice with ligands of TLRs results in the production of interferon-γ and IL-17, hallmarks of T_H1 and T_H17 differentiation, but treatment of mice with ligands of RLRs does not. Furthermore, the physiological relevance of RLR and TLR crosstalk was tested in a mouse model of polymicrobial infection. Consistent with the in vitro results, the splenocytes of mice co-infected with a vesicular stomatitis virus and Listeria monocytogenes expressed much lower levels of IL-12p40 and had substantially higher bacterial loads than mice infected with L. monocytogenes alone. By contrast, IRF3-deficient mice were capable of clearing the bacterial load much more efficiently than wild-type mice, thus supporting the RLR–IRF3 basis of IL-12 suppression in vivo. Finally, an appreciation of such interference in immune signalling is important in order to predict the outcome of infection and for effective management of mixed microbial infections.

Reference

1.         Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291-295 (2010).