Intracellular trafficking, IRF7 and type-I-IFN responses (original) (raw)

Two papers from Tadatsugu Taniguchi's laboratory that were recently published in Nature reveal the importance of the transcription factor interferon (IFN)-regulatory factor 7 (IRF7) in the regulation of type I IFN (IFN-α and IFN-β) responses.

In the first paper, the authors generated IRF7-deficient mice and studied the induction of expression of type I IFNs in these mice. The results showed that IRF7 is essential for the systemic induction of type-I-IFN expression during innate antiviral immune responses (which occurs through a MyD88 (myeloid differentiation primary-response protein 88)-independent signalling pathway), as well as for the local induction of type-I-IFN expression by plasmacytoid DCs (pDCs), which influences CD8+ T-cell-mediated adaptive immune responses (and occurs through the Toll-like receptor (TLR)-activated, MyD88-dependent signalling pathway).

A typical feature of pDCs is their ability to robustly produce large amounts of type I IFNs in response to viruses. But how pDCs, but not conventional DCs (cDCs), can achieve this level of IFN production in response to the same TLR stimuli is not clear. In the second paper, the authors report that this is achieved by spatio-temporal regulation of the MyD88–IRF7-signalling pathway.

To study the cell-type-specific induction of type-I-IFN expression, the authors used confocal microscopy to examine intracellular trafficking of labelled synthetic oligodeoxynucleotides (ODNs). Two different ODNs containing unmethylated CpG motifs were used, CpG-A and CpG-B; both of these signal through TLR9, but they elicit different responses. CpG-A induces a more efficient type-I-IFN response by pDCs than does CpG-B. Using markers to label different cellular compartments, the microscopy results showed that CpG-A is retained for long periods within endosomal vesicles in pDCs, in which MyD88 and IRF7 are co-localized, and this results in sustained activation of the TLR9–MyD88–IRF7-signalling pathway. By contrast, CpG-A in cDCs and CpG-B in pDCs are rapidly transferred to lysosomal vesicles. This endosomal-trafficking model was verified by showing that robust induction of expression of IFN-α and IFN-β could be achieved in cDCs by manipulating the trafficking of CpG-A so that it was similar to that of CpG-A in pDCs. Similarly, it was possible to manipulate CpG-B trafficking in pDCs so that it was retained in endosomal vesicles and could induce robust type-I-IFN production.

Together, these results reveal the importance of IRF7 in the induction of all type-I-IFN responses, and they show that it might be possible to manipulate IFN responses in clinical situations, using compounds that target specific cellular compartments or that alter cellular trafficking.

ORIGINAL RESEARCH PAPERS

  1. Honda, K. et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature 434, 772–777 (2005)
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  2. Honda, K. et al. Spatiotemporal regulation of MyD88–IRF-7 signalling for robust type-I interferon induction. Nature 434, 1035–1040 (2005)
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  1. Elaine Bell
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Bell, E. Intracellular trafficking, IRF7 and type-I-IFN responses.Nat Rev Immunol 5, 361 (2005). https://doi.org/10.1038/nri1625

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