1. Joint Public Review:

    This well-written manuscript describes a spontaneous autoinflammatory phenotype of STAT1-deficient mice, characterized by myeloid hyperplasia, expansion of Th17 cells, microbiota dysbiosis, and inflammatory bowel disease. A similar autoinflammatory condition is seen in humans deficient in STAT1, and in independent colonies of STAT1-deficient mice, but its mechanistic basis is not understood. STAT1 is a critical transcription factor downstream of type I, II (gamma), and III interferon (IFN) signaling. The authors are able to recapitulate the disease phenotype in mice with combined deficiency in both STAT2 (essential for type I and III IFN signaling) and the receptor for IFN gamma, but not in mice deficient in both the type I and II IFN receptors, implying that the phenotype arises from deficiency of all three classes of interferons. Thus the authors conclude that suppression of spontaneous autoinflammatory disease is a redundant function of type I/II/III IFNs. Disease is ameliorated by IL-17 deficiency, indicating a critical role for type 17 responses in pathogenesis. Disease is also ameliorated by treating STAT1 deficient mice with antibiotics, implying a role for the microbiota in the disease progression. The authors' model is that interferons regulate the composition of the microbiota and that dysbiosis of the microbiota then produces the inflammatory disease. The main limitation of the manuscript is that it is not explained how interferons regulate microbiota composition, or how the altered microbiota then produces inflammation. These issues are likely beyond the scope of what could be expected to be fully addressed for this initial paper. However, analysis of disease-free STAT1/IL17-deficient mice could provide insight into whether dysbiosis and inflammation is upstream or downstream of IL-17 signaling.

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  2. Evaluation Summary:

    This manuscript describes a critical function for interferons (IFNs) in suppression of spontaneous autoinflammatory disease. The inflammatory disease is seen in mice lacking all types (I, II, III) of IFN signaling and is ameliorated by deficiency in interleukin-17 as well as by antibiotic treatment. The latter result implies a role for the microbiota in disease pathogenesis, but it remains unclear whether or how IFNs regulate the microbiota composition, whether this occurs across genetic backgrounds or housing conditions, or how exactly IFN deficiency leads to inflammatory disease. Nevertheless this work demonstrates a critical regulatory function for tonic IFN signaling in suppressing autoinflammation that serves as a foundation for future studies and will be of interest to a broad audience of immunologists.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

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