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IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8+ T cell responses to influenza A virus

Abstract

Immune responses to vaccines require direct recognition of pathogen-associated molecular patterns (PAMPs) through pattern-recognition receptors (PRRs) on dendritic cells (DCs). Unlike vaccination, infection by a live pathogen often impairs DC function and inflicts additional damage on the host. Here we found that after infection with live influenza A virus, signaling through the interleukin 1 receptor (IL-1R) was required for productive priming of CD8+ T cells, but signaling through the PRRs TLR7 and RIG-I was not. DCs activated by IL-1 in trans were both required and sufficient for the generation of virus-specific CD8+ T cell immunity. Our data demonstrate a critical role for a bystander cytokine in the priming of CD8+ T cells during infection with a live virus.

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Figure 1: Adaptive immune responses to respiratory IAV that are dependent on and independent of TLR7-MAVS.
Figure 2: IL-1R on hematopoietic cells is required for the activation of CD8+ T cells after infection with influenza virus, but IL-1R on stromal cells is not.
Figure 3: DCs from the mLNs of Il1r1−/− mice are less able to prime naive P14 CD8+ T cells after infection with IAV.
Figure 4: IL-1R signaling promotes the activation of respiratory DCs and their CCR7-dependent migration to the lymph nodes after infection with IAV.
Figure 5: MyD88 signaling in CD11c+ cells is sufficient for DC migration and CD8+ T cell activation after infection with IAV.
Figure 6: Intranasal injection of wild-type DCs restores the priming of CD8+ T cells in Il1r1−/− mice.
Figure 7: Direct activation of caspase-1 in the antigen-presenting DCs is not required for the population expansion of virus-specific CD8+ T cells.

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Acknowledgements

We thank S. Kaech (Yale University) for P14 mice, and H. Dong for technical support. Supported by the US National Institutes of Health (AI062428 and U54 AI057160 to the Midwest Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research).

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I.K.P., T.I. and A.I. conceived of and designed the experiments, and analyzed data; I.K.P. and T.I. did the experiments; and I.K.P. and A.I. wrote the paper.

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Correspondence to Akiko Iwasaki.

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Pang, I., Ichinohe, T. & Iwasaki, A. IL-1R signaling in dendritic cells replaces pattern-recognition receptors in promoting CD8+ T cell responses to influenza A virus. Nat Immunol 14, 246–253 (2013). https://doi.org/10.1038/ni.2514

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