Biology subjects

Küntzel, V.

Publications and source records attributed to Küntzel, V..

2 recordsLinked to original sources

bioRxiv2024

Susceptibility to inflammatory bowel diseases promotes invasive carcinomas in a murine model of ATF6-driven colon cancer

Chronic inflammation in inflammatory bowel disease (IBD) patients represents a risk factor for developing colitis-associated cancer (CAC). We previously linked the endoplasmic reticulum unfolded protein response (UPRER) signal transducer activating transcription factor 6 (ATF6) with spontaneous microbiota-dependent colonic adenoma development in mice expressing epithelial-specific activated ATF6 (nATF6IEC). To investigate IBD-related risk factors in ATF6-mediated tumorigenesis, we crossed tumor-free monoallelic (tg/wt) nATF6IEC mice with Interleukin-10 deficient mice (Il10-/-). IL10 deficiency initiated tumor susceptibility, with 77% of 12-week tg/wt;Il10-/- mice developing colonic adenomas and invasive carcinomas in this novel CAC mouse model. Tumor formation correlated with mucosal immune cell infiltration, characterized by CD11b+ granulocytes and monocytes, and mucosa-associated dysbiosis. Colonization of germ-free nATF6IEC;Il10-/- mice with minimal biosynthetic consortia and IBD stool re-established CAC, confirming microbiota-dependent ATF6-driven tumorigenesis. Increased ATF6 expression in IBD patients during active disease highlights its human relevance. Our findings show that IBD susceptibility heightens the risk for ATF6-driven tumorigenesis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/624835v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@17e280eorg.highwire.dtl.DTLVardef@177ceacorg.highwire.dtl.DTLVardef@a1916borg.highwire.dtl.DTLVardef@152374f_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Cross-species analyses reveal RORγt-expressing dendritic cells are a lineage of antigen presenting cells conserved across tissues

Conventional dendritic cells (cDCs) are potent antigen presenting cells (APCs) that exhibit tissue and age-specific diversity allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination and cancer. Here, we resolve conflicting data about expression of retinoic acid receptor-related orphan receptor-{gamma}t (ROR{psi}t) in cDCs. We show that ROR{psi}t+ DCs exist in murine lymphoid and non-lymphoid tissues across age. Fate mapping, functional assays and single cell multiomic profiling reveal these cells as ontogenetically and transcriptionally distinct from other well characterized cDC subtypes, as well as from ROR{psi}t+ type 3 innate lymphocytes (ILC3s). We show that ROR{psi}t+ DCs can migrate to lymph nodes and activate naive CD4+ T cells in response to inflammatory triggers. Comparative and cross-species transcriptomics revealed homologous populations in human spleen, lymph nodes and intestines. Further, integrated meta-analyses aligned ROR{psi}t+ DCs identified here with other emerging populations of ROR{psi}t+APCs, including R-DC-like cells, Janus cells/extrathymic Aire expressing cells (eTACs) and subtypes of Thetis cells. While ROR{psi}t+APCs have primarily been linked to T cell tolerance, our work establishes ROR{psi}t+ DCs as unique lineage of immune sentinel cells conserved across tissues and species that expands the functional repertoire of ROR{psi}t+ APCs beyond promoting tolerance. One sentence summaryROR{gamma}t+ DC exhibit versatile APC functions and are a distinct immune lineage conserved across age, tissues and species that entails Thetis cells, Janus cells/ROR{gamma}t+ eTACs and R-DC-like cells.

immunology↗