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Celiac disease has previously been regarded as a benign intestinal disorder that can be easily treated by a gluten-free diet. This Review article discusses advances in the understanding of the genetics and immunology of celiac disease, and considers evidence for the independent existence of the adaptive and innate immune response to gluten.

If an exogenous antigen such as gluten can drive the autoimmune features of coeliac disease, such as the production of autoantibodies and the destruction of a specific tissue type, should we be looking more closely at the possibility that other autoimmune diseases are driven by exogenous, not self, antigens?

This Opinion article proposes that interleukin-15 (IL-15) is a master regulator of tissue-specific T cell responses to promote the destruction of infected cells. Hence, dysregulation of IL-15 production in tissues during sterile inflammation can lead to T cell-mediated autoimmunity.

Sepsis due to multidrug resistant pathogens is the most common cause of death in intensive care units. Here, the authors report that fecal microbiota transplant (FMT) can rescue mice from lethal sepsis of pathogens isolated from stool of a critically ill patient and show that FMT reverses the immunosuppressive effect induced by the pathogen community.

IFNγ signalling in epithelial cells promotes antigen presentation that confers intra-epithelial T cells the ability to limit extracellular ATP and consequent NLRP3 inflammasome activation, controlling pathogenic transformation of CD4⁺ T cells that promotes colitis and colorectal cancer in mouse models.

Bendelac, McDonald and colleagues show that the NK cell-committed precursor in the mouse bone marrow expresses the transcription factor Eomes.

Studies using genetic tools have identified the distinct dendritic cell subsets that ensure tolerance to oral antigens in the antigen-rich environment of the gut and suggest a 'division of labor' for protective immunity.

The kinase LRRK2 is a risk factor for inflammatory bowel disease. New data show that LRRK2 blocks the transport of NFAT to the nucleus and that LRRK2 deficiency results in enhanced susceptibility to experimental colitis in mice.

Consumption of a diet high in milk-derived fat is shown to increase the abundance of sulphite-reducing bacteria by altering bile composition, leading to inflammation and colitis in genetically susceptible mice.

Genome-wide association studies have identified genes encoding major histocompatibility (MHC) class II molecules as the single most important predisposing factor for autoimmunity. A new study provides atomic insight into how the antigen receptors of intestinal T cells recognize dietary gluten that drives celiac disease pathogenesis when bound to the MHC class II molecule HLA-DQ2.5, the major genetic risk factor of celiac disease.

Emerging evidence indicates that the gut microbiota might have a role in the development of coeliac disease. In this Review, Verdu and colleagues describe how alterations in the composition and function of the gut microbiota might influence coeliac disease pathogenesis, presenting the latest data from human and experimental studies.

Coeliac disease results from an inappropriate response to dietary gluten. In this Review, the authors describe the ways in which intestinal tissue cells contribute to the inflammatory environment that leads to the induction of a tissue-destructive, gluten-specific T cell response.

Halper-Stromberg and Jabri discuss the molecular and functional adaptations to inflammatory or pathogenic stimuli that shape the immune identity of each individual.

This work introduces microbial-enrichment methodology (MEM) that enables removal of host DNA in human intestinal biopsies and characterization of low-abundance microbial taxa down to 1%.

An HLA- and gluten-dependent mouse model of coeliac disease with villous atrophy provides evidence for the cooperative role of IL-15 and gluten-specific CD4⁺ T cells in licensing the full activation of cytotoxic T cells that are necessary for inducing epithelial damage.

Multiomics analysis of right colon tissues identifies a distinct immune gene signature associated with greater risk of and shorter time to dysplasia in patients with primary sclerosing cholangitis, but not in patients with inflammatory bowel disease.

Gluten peptides from wheat enter the bloodstream and are excreted in urine but are yet to be chemically characterised. Here, the authors show by mass spectrometry that quantitative and qualitative differences in urinary peptides can be detected between healthy people and patients with celiac disease.

Gluten triggers celiac disease in genetically predisposed individuals, but additional unknown mechanisms are required. Here, the authors show that proteases from Pseudomonas aeruginosa can modulate inflammatory pathways that are relevant to the development of food sensitivities, independently of the trigger antigen.

Here Ramanan and colleagues provide an analysis of mammary T cells during late pregnancy and lactation. This revealed an increase in intraepithelial lymphocytes in the lactating mammary gland, which was driven by thymic and intestinal inputs and was sensitive to changes in the microbiota

The association of particular major histocompatibility complex (MHC) polymorphisms with susceptibility to a number of autoimmune disease has been a puzzling phenomenon. This paper proposes a mechanism that might account in part for the onset of coeliac disease. Transaminase-mediated deamination of glutamine residues in gluten peptides may cause them to bind more tightly to disease-associated MHC alleles, activating heteroclitic gluten-peptide specific T-cell autoreactivity in the gut.

Microbial signals are crucial to the development of pre-leukaemic myeloproliferation, which can be induced by disrupting the intestinal barrier or by introducing systemic bacterial stimuli in Tet2-deficient mice.

This Review provides an overview of our current understanding of the unconventional T cell compartment and discusses the development and function of unconventional T cells from an evolutionary perspective.

In this Review, the authors discuss how the gut microbiota might incite food sensitivity. They focus on direct and indirect mechanisms involving microorganisms and how increased understanding of these mechanisms will help the development of therapeutic strategies for food sensitivities.

The intestine harbours a complex array of intraepithelial lymphocytes that patrol the epithelial layer and exert rapid cytolytic function. Here, the authors compare the different cytolytic populations and suggest that this diversity results from evolutionary pressure to protect this important barrier.