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

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Although the mechanisms by which innate pathogen-recognition receptors enhance adaptive immune responses are increasingly well understood, whether signaling events from distinct classes of receptors affect each other in modulating adaptive immunity remains unclear. We found here that the activation of cytosolic RIG-I-like receptors (RLRs) resulted in the selective suppression of transcription of the gene encoding the p40 subunit of interleukin 12 (Il12b) that was effectively induced by the activation of Toll-like receptors (TLRs). The RLR-activated transcription factor IRF3 bound dominantly, relative to IRF5, to the Il12b promoter, where it interfered with the TLR-induced assembly of a productive transcription-factor complex. The activation of RLRs in mice attenuated TLR-induced responses of the T helper type 1 cell (TH1 cell) and interleukin 17–producing helper T cell (TH17 cell) subset types and, consequently, viral infection of mice caused death at sublethal doses of bacterial infection. The innate immune receptor cross-interference we describe may have implications for infection-associated clinical episodes.

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Figure 1: Cytokine-expression profiles after activation of PRRs.
Figure 2: Binding of IRF3 to the Il12b promoter after activation of RLRs.
Figure 3: IRF5-dependent induction of Il12b in IRF3-deficient cells after stimulation of RLRs.
Figure 4: RLR-activated IRF3 interferes with the TLR-activated productive transcription complex.
Figure 5: IRF3-mediated suppression of Il12b induction by RLR signaling.
Figure 6: T cell polarization induced by PRR signaling or microbial infection.
Figure 7: Suppression of Il12b induction and enhancement of susceptibility to bacteria by the virus-RLR-IRF3 axis.

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We thank R. Medzhitov, A. Iwasaki, J. Ravetch, D. Savitsky and H. Rosen for advice; M. Kubo, M. Yoneyama, S. Nakae, S. Kano, F. Ohtake, H. Tani, N. Atarashi, M. Matsumoto, K. Nakayama and T. Negishi for discussions; and T. Ban, N. Endo, T. Kawaguchi, R. Takeda, M. Taniguchi and M. Shishido for technical assistance. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant-In-Aid for Scientific Research on Innovative Areas, Global Center of Excellence Program 'Integrative Life Science Based on the Study of Biosignaling Mechanisms'), the Japan Science and Technology Agency (Core Research for Evolutional Science and Technology) and the Japan Society for the Promotion of Science (A.N. and R.K.).

Author information

H.N., H.Y., A.N., R.K., K.A. and K.H. designed, did and analyzed most of the experiments; A.N. and A.M. did ChIP assays; K.M., S.M. and J.N. did viral infection and RT-PCR experiments; A.A., T.D. and S.T.S. provided materials and advice for specific experiments; and T.T. provided overall coordination for the conception, design and supervision of the study and wrote the manuscript (with input from H.N., H.Y., A.N. and K.H.).

Correspondence to Tadatsugu Taniguchi.

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Negishi, H., Yanai, H., Nakajima, A. et al. Cross-interference of RLR and TLR signaling pathways modulates antibacterial T cell responses. Nat Immunol 13, 659–666 (2012) doi:10.1038/ni.2307

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