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.

Bacterial cell gene expression: Single-cell genomics in bacteria has lagged relative to in eukaryotes because of their tough bacterial cell walls, low messenger RNA content, and lack of many posttranscriptional modifications. To tackle this challenge, Kuchina et al. developed microbial split-pool ligation transcriptomics, or microSPLiT, a single-cell sequencing method for both Gram-negative and Gram-positive bacteria. Sequencing both Escherichia coli and Bacillus subtilis showed differences in the heat shock response. Examining B. subtilis transcriptional patterns revealed that a small fraction of cells grown in laboratory medium express a myo-inositol catabolism pathway, which the cell could use in nonlaboratory environments, thus highlighting how microSPLiT can identify rare cellular states. Science , this issue p. eaba5257

The plague is caused by the bacterium Yersinia pestis . Plague bacteria are thought to inject effector Yop proteins into host cells via the type III pathway. The identity of the host cells targeted for injection during plague infection is unknown. We found, using Yop β-lactamase hybrids and fluorescent staining of live cells from plague-infected animals, that Y. pestis selected immune cells for injection. In vivo, dendritic cells, macrophages, and neutrophils were injected most frequently, whereas B and T lymphocytes were rarely selected. Thus, it appears that Y. pestis disables these cell populations to annihilate host immune responses during plague.

Yersinia pestis, the causative agent of plague, secretes LcrV (low-calcium-response V or V antigen) during infection. LcrV triggers the release of interleukin 10 (IL-10) by host immune cells and suppresses proinflammatory cytokines such as tumor necrosis factor alpha and gamma interferon as well as innate defense mechanisms required to combat the pathogenesis of plague. Although immunization of animals with LcrV elicits protective immunity, the associated suppression of host defense mechanisms may preclude the use of LcrV as a human vaccine. Here we show that short deletions within LcrV can reduce its immune modulatory properties. An LcrV variant lacking amino acid residues 271 to 300 (rV10) elicited immune responses that protected mice against a lethal challenge withY. pestis. Compared to full-length LcrV, rV10 displayed a reduced ability to release IL-10 from mouse and human macrophages. Furthermore, the lipopolysaccharide-stimulated release of proinflammatory cytokines by human or mouse macrophages was inhibited by full-length LcrV but not by the rV10 variant. Thus, it appears that LcrV variants with reduced immune modulatory properties could be used as a human vaccine to generate protective immunity against plague.