Intestinal microbiota sustains inflammation and autoimmunity induced by hypomorphic RAG defects

Omenn syndrome (OS) is caused by hypomorphic Rag mutations and characterized by a profound immunodeficiency associatedwith autoimmune-like manifestations. Both in humans and mice, OS is mediated by oligoclonal activated T and B cells. Therole of microbial signals in disease pathogenesis is debated. Here, we show that Rag2R229Q knock-in mice developed an inflammatorybowel disease affecting both the small bowel and colon. Lymphocytes were sufficient for disease induction, as intestinalCD4 T cells with a Th1/Th17 phenotype reproduced the pathological picture when transplanted into immunocompromisedhosts. Moreover, oral tolerance was impaired in Rag2R229Q mice, and transfer of wild-type (WT) regulatory T cells amelioratedbowel inflammation. Mucosal immunoglobulin A (IgA) deficiency in the gut resulted in enhanced absorption of microbial productsand altered composition of commensal communities. The Rag2R229Q microbiota further contributed to the immunopathologybecause its transplant into WT recipients promoted Th1/Th17 immune response. Consistently, long-term dosing ofbroad-spectrum antibiotics (ABXs) in Rag2R229Q mice ameliorated intestinal and systemic autoimmunity by diminishing thefrequency of mucosal and circulating gut-tropic CCR9+ Th1 and Th17 T cells. Remarkably, serum hyper-IgE, a hallmark of thedisease, was also normalized by ABX treatment. These results indicate that intestinal microbes may play a critical role in thedistinctive immune dysregulation of OS.