Programmed recognition of microbiota: Increasingly, we recognize that the gut is a specialized organ for maintaining microbial symbioses alongside nutritional functions. The gut produces large quantities of immunoglobulin A (IgA), which adheres to the surface of gut microbes. Bunker et al. discovered that antibodies produced by naïve small intestinal plasma cells are recirculated and enriched within Peyer's patches, independently of exogenous antigen and T cell help. The resulting polyreactive IgAs are released into the gut lumen and bind to microbial surface glycans, thus innately recognizing the gut microbiota. Polyreactive IgAs appear to be a product of the coevolution of host and microbiota to maintain symbiotic homeostasis. Science , this issue p. eaan6619

Celiac disease (CD) is a gluten-sensitive enteropathy that develops in genetically susceptible individuals by exposure to cereal gluten proteins. This review integrates insights from immunological studies with results of recent genetic genome-wide association studies into a disease model. Genetic data, among others, suggest that viral infections are implicated and that natural killer effector pathways are important in the pathogenesis of CD, but most prominently these data converge with existing immunological findings that CD is primarily a T cell–mediated immune disorder in which CD4⁺T cells that recognize gluten peptides in the context of major histocompatibility class II molecules play a central role. Comparison of genetic pathways as well as genetic susceptibility loci between CD and other autoimmune and inflammatory disorders reveals that CD bears stronger resemblance to T cell–mediated organ-specific autoimmune than to inflammatory diseases. Finally, we present evidence suggesting that the high prevalence of CD in modern societies may be the by-product of past selection for increased immune responses to combat infections in populations in which agriculture and cereals were introduced early on in the post-Neolithic period.

Viral infections have been proposed to elicit pathological processes leading to the initiation of T helper 1 (T_H1) immunity against dietary gluten and celiac disease (CeD). To test this hypothesis and gain insights into mechanisms underlying virus-induced loss of tolerance to dietary antigens, we developed a viral infection model that makes use of two reovirus strains that infect the intestine but differ in their immunopathological outcomes. Reovirus is an avirulent pathogen that elicits protective immunity, but we discovered that it can nonetheless disrupt intestinal immune homeostasis at inductive and effector sites of oral tolerance by suppressing peripheral regulatory T cell (pT_reg) conversion and promoting T_H1 immunity to dietary antigen. Initiation of T_H1 immunity to dietary antigen was dependent on interferon regulatory factor 1 and dissociated from suppression of pT_reg conversion, which was mediated by type-1 interferon. Last, our study in humans supports a role for infection with reovirus, a seemingly innocuous virus, in triggering the development of CeD.

Somatic mutations in tet methylcytosine dioxygenase 2 (TET2), which encodes an epigenetic modifier enzyme, drive the development of haematopoietic malignancies^{1,2,3,4,5,6,7}. In both humans and mice, TET2 deficiency leads to increased self-renewal of haematopoietic stem cells with a net developmental bias towards the myeloid lineage^1,4,8,9. However, pre-leukaemic myeloproliferation (PMP) occurs in only a fraction of Tet2^−/− mice^8,9 and humans with TET2 mutations^1,3,5,6,7, suggesting that extrinsic non-cell-autonomous factors are required for disease onset. Here we show that bacterial translocation and increased interleukin-6 production, resulting from dysfunction of the small-intestinal barrier, are critical for the development of PMP in mice that lack Tet2 expression in haematopoietic cells. Furthermore, in symptom-free Tet2^−/− mice, PMP can be induced by disrupting intestinal barrier integrity, or in response to systemic bacterial stimuli such as the toll-like receptor 2 agonist. PMP was reversed by antibiotic treatment and failed to develop in germ-free Tet2^−/− mice, which illustrates the importance of microbial signals in the development of this condition. Our findings demonstrate the requirement for microbial-dependent inflammation in the development of PMP and provide a mechanistic basis for the variation in PMP penetrance observed in Tet2^−/− mice. This study will prompt new lines of investigation that may profoundly affect the prevention and management of haematopoietic malignancies.

The vitamin A metabolite retinoic acid is shown to act synergistically with the cytokine interleukin-15 (IL-15) to induce IL-12p70 production by intestinal dendritic cells, thereby promoting an inflammatory T-cell response to dietary antigens. IL-15 is upregulated in the guts of patients with coeliac disease, and this new work points to a previously unknown involvement of IL-15 and retinoic acid in promoting an inflammatory immune response to gluten. The vitamin A metabolite retinoic acid is shown to act in conjunction with IL-15 to induce IL-12p70 production by intestinal dendritic cells, thereby promoting an inflammatory T-cell response to dietary antigens. The mechanism may underlie coeliac disease pathogenesis. Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens1,2. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat3. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses4,5,6. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients3,7, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.