The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function.

The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4+ T cells; however, its cell-intrinsic role in CD8+ T cells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ T cell (TRM) differentiation and function. Genetic ablation of Ahr in mouse CD8+ T cells leads to increased CD127-KLRG1+ short-lived effector cells and CD44+CD62L+ T central memory cells but reduced granzyme-B-producing CD69+CD103+ TRM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ T cell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8+ T cells also highly express AHR that regulates in vitro TRM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ T cell immunity.

The microbial genotoxin colibactin exacerbates mismatch repair mutations in colorectal tumors.

Certain Enterobacteriaceae strains contain a 54-kb biosynthetic gene cluster referred to as "pks" encoding the biosynthesis of a secondary metabolite, colibactin. Colibactin-producing E. coli promote colorectal cancer (CRC) in preclinical models, and in vitro induce a specific mutational signature that is also detected in human CRC genomes. Yet, how colibactin exposure affects the mutational landscape of CRC in vivo remains unclear. Here we show that colibactin-producing E. coli-driven colonic tumors in mice have a significantly higher SBS burden and a larger percentage of these mutations can be attributed to a signature associated with mismatch repair deficiency (MMRd; SBS15), compared to tumors developed in the presence of colibactin-deficient E. coli. We found that the synthetic colibactin 742 but not an inactive analog 746 causes DNA damage and induces transcriptional activation of p53 and senescence signaling pathways in non-transformed human colonic epithelial cells. In MMRd colon cancer cells (HCT 116), chronic exposure to 742 resulted in the upregulation of BRCA1, Fanconi anemia, and MMR signaling pathways as revealed by global transcriptomic analysis. This was accompanied by increased T>N single-base substitutions (SBS) attributed to the proposed pks+E. coli signature (SBS88), reactive oxygen species (SBS17), and mismatch-repair deficiency (SBS44). A significant co-occurrence between MMRd SBS44 and pks-associated SBS88 signature was observed in a large cohort of human CRC patients (n=2,945), and significantly more SBS44 mutations were found when SBS88 was also detected. Collectively, these findings reveal the host response mechanisms underlying colibactin genotoxic activity and suggest that colibactin may exacerbate MMRd-associated mutations.

Microbial host interactions in IBD: implications for pathogenesis and therapy.

Crohn's disease (CD), ulcerative colitis (UC), and pouchitis appear to be caused by pathogenic T-cell responses to discrete antigens from the complex luminal microbiota, with susceptibility conferred by genetic polymorphisms that regulate bacterial killing, mucosal barrier function, or immune responses. Environmental triggers initiate or reactivate inflammation and modulate genetic susceptibility. New pathogenesis concepts include defective bacterial killing by innate immune cells in CD, colonization of the ileum in CD with functionally abnormal Escherichia coli that adhere to and invade epithelial cells and resist bacterial killing, and alterations in enteric microbiota composition in CD, UC, and pouchitis detected by molecular probes. The considerable therapeutic potential of manipulating the enteric microbiota in inflammatory bowel disease patients has not been realized, probably due to failure to recognize heterogenic disease mechanisms that require individualized use of antibiotics, probiotics, prebiotics, combination therapies, and genetically engineered bacteria to restore mucosal homeostasis.