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The effects of climate change driven by human activity are now part of the daily news cycle, and time is running out for decisive action.

Mucida and colleagues examine how the gut epithelial microenvironment alters CD4⁺ T cells during their conversion into intraepithelial lymphocytes. They reveal a stepwise process involving chromatin accessibility and transcription changes triggered by ThPOK downregulation.

CD4⁺ and CD8⁺ T cells are considered distinct functional lymphocyte subsets. Cheroutre and Mucida and their colleagues show that mature gut-associated CD4⁺ T cells lose ThPOK expression and reactivate CD8 cytolytic effector programs.

CD4⁺ and CD8⁺ T cells are considered distinct functional lymphocyte subsets. Cheroutre and Mucida and their colleagues show that mature gut-associated CD4⁺ T cells lose ThPOK expression and reactivate CD8 cytolytic effector programs.

The subsets of antigen presenting cells (APCs) that mediate tolerance to oral antigens remain unclear. Mucida and colleagues use lineage-specific depletion of APCs to show that monocyte-derived APCs are dispensable, while classical dendritic cells are critical, for the induction of regulatory T cells and oral tolerance.

Antibody selection and maturation within B cells found in gut-associated germinal centres is stimulated by the gut microbiota, to a degree that depends on the presence and composition of the microbes.

The gut is an active site of immune defence against disease-causing microbes. A study in mice shows that a type of immune cell in the gut’s wall also helps to regulate sugar and fat metabolism.

A combination of gnotobiotic mouse models, transcriptomics, circuit tracing and chemogenetic manipulations identifies neuronal circuits that integrate microbial signals in the gut with regulation of the sympathetic nervous system.

Cas9 DNA targeting is inherently sequence specific but not temporally controlled. Here, authors spatiotemporally couple Cas9 activity to target site transcription in eukaryotes and exploit this to preferentially edit the more highly transcribed of two alleles that harbor identical Cas9 targets.

In the intestine, intraepithelial lymphocytes (IELs) maintain the integrity of the epithelial barrier and provide protection against pathogens. However, IELs may also drive immunopathological responses in patients with coeliac disease or inflammatory bowel disease. Here, the authors discuss the 'light' and 'dark' sides of the intestinal IELs.

Therapeutic interventions in colorectal cancer are dependent on immune responses to dying epithelial cells that are modulated by specific members of the gut microbiota.

A paper reports the development of a universal tool for studying cellular interactions in biological systems, and demonstrates its coupling with single-cell transcriptomics methods to provide insights into the biology of the interactions.

Agonist encounter can divert thymocytes into several unconventional T cell subsets, many of which exhibit regulatory properties. Unexpected findings indicate that agonist selection can drive the differentiation of interleukin 17–producing cells in the thymus.

Immune responses in the gut and associated draining lymph nodes differ between tolerogenic and inflammatory depending on their anatomical location.

Gates et al. show that histone butyrylation and propionylation in the intestinal epithelium are regulated by the gut microbiota and histone butyrylation is associated with gene regulatory programmes.

Peripheral CD4⁺ T cells can develop into Intestinal intraepithelial lymphocytes (IEL) in the lamina propria. Here the authors characterise how IEL generation from CD4⁺ T cells is regulated and show using scRNA sequencing that Ccr9 is involved in this process through limiting IEL precursor differentiation.

Intraepithelial lymphocytes expressing γ and δ T cell receptor subunits protect Paneth cells from cell death caused by viral infection or Crohn's disease.

Sestan et al. find a conserved mechanism during systemic viral infection in which γδ T cells produce IFNγ to increase pancreatic insulin secretion, lowering blood glucose and then enhancing type I interferon-mediated protection against viral infection.

The transcription factor ThPOK is critical for homeostasis and differentiation of mature helper T cells. Here, Kappes and colleagues describe a ThPOK-mediated positive autoregulatory loop that is crucial for tissue-specific T_reg cell differentiation, maintenance of intestinal T_reg cell integrity and conversion of these cells into CD4⁺ intraepithelial lymphocytes.

A consortium of 11 bacterial strains from the healthy human gut microbiota can strongly induce interferon-γ-producing CD8 T cells in the intestine, and enhance both resistance to bacterial infection and the therapeutic efficacy of immune checkpoint inhibitors.

A longitudinal analysis of humoral immune responses in patients with COVID-19 with varying disease severities reveals that mortality does not correlate with antiviral antibody levels but, instead, with slower seroconversion.

A longitudinal analysis of immune responses in patients with moderate or severe COVID-19 identifies a maladapted immune response profile linked to severe disease.

Integrin β7-dependent Glp1r^high natural gut intraepithelial T lymphocytes that reside in the small intestine modulate dietary metabolism in mice by restricting the bioavailability of GLP-1.

Woolf and colleagues use single-cell transcriptomics to determine the gene signature of infiltrating immune cells and potential cell–cell interactions between receptors, ligands, ion channels and metabolites expressed on immune cells and sensory neurons in three models of pain.

In a mouse model of colorectal cancer, barrier deterioration results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives IL-23-dependent tumour growth.