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Bruder, K.

Publications and source records attributed to Bruder, K..

2 recordsLinked to original sources

Postnatal Maturation of Dendritic Epidermal T Cells and Langerhans Cells Follows Distinct Differentiation Trajectories Independent of Microbiota

The mouse epidermis harbors two key resident immune populations--dendritic epidermal T cells (DETCs), a subset of invariant {gamma}{delta} T cells, and Langerhans cells (LCs), specialized tissue-resident macrophages--both of which play critical roles in immune surveillance, barrier integrity, and tissue homeostasis. While the fetal origin of both cell types has been defined, the cellular and molecular mechanisms that govern their postnatal fates following colonization of the epidermis around birth remain incompletely understood. Here, we present a combination of immunophenotyping- and transcriptome-resolved single-cell map of DETC and LC development in the mouse epidermis from late embryogenesis through adulthood. We delineate differentiation trajectories for both cell types, marked by distinct changes in morphology, proliferation, and transcriptional programming. Using mice deficient in {gamma}{delta} T cells, which lack canonical DETCs, we demonstrate that LCs develop independently of canonical DETCs likely due to the presence of {beta}DETCs. Moreover, analysis of germ-free mice and wildlings reveals that the postnatal development of both DETCs and LCs is independent of microbial colonization. Together, our findings define the core principles underlying the establishment of the mouse epidermal immune niche. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/716534v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@18088a0org.highwire.dtl.DTLVardef@189e0f2org.highwire.dtl.DTLVardef@10f37d6org.highwire.dtl.DTLVardef@1ad59c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Colibactin-producing E. coli promote carcinogenesis of gastroesophageal adenocarcinoma and simultaneously induce autophagy and differentiation

Background & AimsGastroesophageal adenocarcinoma (GEAC) is a malignancy of the gastroesophageal junction (GEJ) and is associated with reflux of gastroduodenal contents and Barretts Esophagus (BE). A shift towards gram-negative bacteria in the microbiota of the GEJ additionally promotes inflammation and likely carcinogenesis. Enterobacteriaceae are enriched in advanced stages of GEAC development, and members of this family can produce colibactin, a genotoxin implicated in DNA damage and tumor progression. We aimed to validate these observations and investigate the effect of E. coli with or without colibactin production on GEAC-carcinogenesis. MethodsBacteria were profiled in human biopsies with imaging and 16S rRNA gene sequencing. Organoids of our L2-IL1B mouse model of GEAC were exposed to E. coli with colibactin (CoPEC) and without colibactin production (noCoPEC) via organoid microinjection. The phenotypic and transcriptomic changes in the organoids after the coculture with E. coli were evaluated via histology and single-cell RNA sequencing. ResultsIn human specimens, we observed an infiltration of bacteria in GEJ-tissue upon tumor formation and detected Enterobacteriaceae in one third of BE-patients. CoPEC-injected organoids exhibited high rates of proliferation and DNA damage, and an upregulation of cancer-associated genes and pathways. Furthermore, genes and pathways associated with immune activation, defense mechanisms, metabolic reprogramming, autophagy and differentiation were upregulated in CoPEC-injected organoids. ConclusionIn addition to the enrichment of Enterobacteriaceae in the GEJ-tissue of patients at late stages of GEAC, we show that the exposure of colibactin-producing E. coli to murine BE-organoids promotes genetic instability and proliferation, and the activation of cancer-associated pathways, while also activating autophagy and enhancing intercellular homeostasis. This indicates that colibactin-producing E. coli have a dual effect on early stages of GEAC-carcinogenesis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/687579v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1281a14org.highwire.dtl.DTLVardef@1c83c91org.highwire.dtl.DTLVardef@10088d2org.highwire.dtl.DTLVardef@1698a2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗