Biology subjects

Komnick, M. R.

Publications and source records attributed to Komnick, M. R..

3 recordsLinked to original sources

bioRxiv2025

Tissue-specific tolerance mechanisms and lymph node co-drainage converge to shape T cell immunity in the upper digestive system and regulate pancreatic cancer progression

The liver, pancreas, and duodenum share lymph nodes (LNs), providing a unique system to examine how tissue origin of self-antigens shapes T cell fate. Comparing mice expressing ovalbumin (OVA) from distinct subcellular compartments, we found that cytosolic OVA from liver or pancreas, but not gut, was immunologically ignored. High-dose hepatic secreted OVA triggered antigen-specific T cell deletion, whereas secreted pancreatic and intestinal OVA induced regulatory T (Treg) cells, revealing immunological ignorance, clonal deletion and Treg cell generation as tissue-specific tolerance mechanisms. Of these, LN co-drainage only influenced Treg cell induction, establishing gut-pancreas-liver axes: Intestinal viral infection rendered hepatocyte- and exocrine pancreas-specific T cells inflammatory; liver injury promoted pancreas- and gut-directed responses. These self-reactive T cells caused tissue destruction but enhanced pancreatic tumor control when neoantigen OVA was secreted but not cytosolic. Thus, LN co-drainage and tissue-specific tolerance mechanisms jointly shape immune homeostasis and disease susceptibility in the upper digestive system.

immunology↗

bioRxiv2025

T cell fate is dictated by different antigen presenting cells in response to dietary versus gut epithelial self-antigen

We investigated whether T cell responses and antigen-presenting cell (APC) requirements in gut-draining lymph nodes differ by antigen source, diet versus epithelium. Using mice fed ovalbumin (OVA) or expressing secreted (s), cytosolic (c), or transmembrane (tm) epithelial OVA, we compared OVA-specific T cell fates. At baseline and after reovirus infection, T cell responses were comparable across models. However, helminth infection induced Th2 cell polarization in sOVA and tmOVA but not cOVA or OVA-fed mice. BATF3 APCs were indispensable for CD4 T cell proliferation only in cOVA mice yet drove Treg cell differentiation across all epithelial OVA models. In contrast, antigen presentation by ROR{gamma}tMHC-II APCs was exclusively required for Treg cell induction by dietary OVA. These distinct APC dependencies correlated with susceptibility to pathology elicited by dietary versus epithelial self-antigens. Thus, antigen origin and presentation context are integrated to shape T cell fate, a new framework for predicting gut immune outcomes.

immunology↗

bioRxiv2024

Inducible, but not constitutive, pancreatic REG/Reg isoforms are regulated by intestinal microbiota and pancreatic diseases

The REG/Reg gene locus encodes for a conserved family of potent antimicrobial but also pancreatitis-associated proteins. Here we investigated whether REG/Reg family members differ in their baseline expression levels and abilities to be regulated in the pancreas and gut upon perturbations. We found, in human and mouse, pancreas and gut differed in REG/Reg isoform levels and preferences, with duodenum most resembling the pancreas. Pancreatic acinar cells and intestinal enterocytes were the dominant REG producers. Intestinal symbiotic microbes regulated the expression of the same, select Reg members in gut and pancreas. These Reg members had the most STAT3-binding sites close to the transcription start sites and were partially IL-22 dependent. We thus categorized them as "inducible" and others as "constitutive". Indeed, also in models of pancreatic-ductal adenocarcinoma and pancreatitis, only inducible Reg members were upregulated in pancreas. While intestinal Reg expression remained unchanged upon pancreatic perturbation, pancreatitis altered the microbial composition of the duodenum and feces shortly after disease onset. Our study reveals differential usage and regulation of REG/Reg isoforms as a mechanism for tissue-specific innate immunity, highlights the intimate connection of pancreas and duodenum, and implies a gut-to-pancreas communication axis resulting in a coordinated Reg response.

immunology↗