Biology subjects

Dermody, T.

Publications and source records attributed to Dermody, T..

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↗

bioRxiv2020

Enteric viruses evoke broad host immune responses resembling bacterial microbiome

Contributions of the viral component of the microbiome, the virome, to the development of innate and adaptive immunity are largely unknown. Here, we systematically defined the host response in mice to a panel of eukaryotic enteric viruses representing six different families. Most of these viruses asymptomatically infected the mice, the magnitude and duration of which was dependent on the microbiota. Flow cytometric and transcriptional profiling of mice mono-associated with these viruses unveiled general adaptations by the host, such as lymphocyte differentiation and IL-22 signatures in the intestine as well as numerous viral strain-specific responses that persist. Comparison with a dataset derived from analogous bacterial mono-association mice identified bacterial species that evoke an immune response comparable to the viruses we examined. These results expand an understanding of the immune space occupied by the enteric virome and underscore the importance of viral exposure events.

microbiology↗

bioRxiv2020

Neuron-intrinsic NF-κB Signaling Mediates Reovirus Virulence

Pathological effects of apoptosis associated with viral infections of the central nervous system are an important cause of morbidity and mortality. Reovirus is a neurotropic virus that causes apoptosis in neurons, leading to lethal encephalitis in newborn mice. Reovirus-induced encephalitis is diminished in mice with germline ablation of NF-{kappa}B subunit p50. It is not known whether the pro-apoptotic function of NF-{kappa}B is mediated by neuron-intrinsic processes, NF-{kappa}B-regulated cytokine production by inflammatory cells, or a combination of both. To determine the contribution of cell type-specific NF-{kappa}B signaling in reovirus-induced neuronal injury, we established mice that lack NF-{kappa}B p65 expression in neurons using the Cre/loxP recombination system. Following intracranial inoculation of reovirus, 50% of wild-type (WT) mice succumbed to infection, whereas more than 90% of mice lacking neural NF-{kappa}B p65 (Nsp65-/-) mice survived. While viral loads in brains of WT and Nsp65-/- were comparable, histological analysis revealed that reovirus antigen-positive areas in the brain of WT mice displayed enhanced cleaved caspase-3 immunoreactivity, a marker of apoptosis, compared with Nsp65-/- mice. These data suggest that neuron-intrinsic NF-{kappa}B-dependent factors are essential mediators of reovirus neurovirulence. RNA sequencing analysis of reovirus-infected cortices of WT and Nsp65-/- mice suggests that NF-{kappa}B activation in neurons upregulates genes involved in innate immunity, inflammation, and cell death following reovirus infection. A better understanding of the contribution of cell type-specific NF-{kappa}B-dependent signaling to viral neuropathogenesis could inform development of new therapeutics that target and protect highly vulnerable cell populations

microbiology↗