Biology subjects

Esterhazy, D.

Publications and source records attributed to Esterhazy, D..

5 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↗

bioRxiv2022

Identification of dendritic cell-T cell interactions driving immune responses to food

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Dendritic cells (DCs) orchestrate these immune responses by presenting luminal antigens and inducing functional differentiation of CD4+ T cells into regulatory (pTreg) or pro-inflammatory (Th) subsets. However, the exact nature of the DCs inducing tolerance or inflammation to dietary antigens has been difficult to define. Using an intestine-adapted Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC) combined with single-cell transcriptomics, we characterized DCs presenting dietary antigens in the context of tolerance or infection. At steady-state, migratory cDC1 and cDC2 DCs, but not resident DCs, were found to present dietary antigen to cognate CD4+ T cells. Whereas cDC2s promoted T cell activation, only cDC1s induced their differentiation into pTregs. Infection with the helminth Strongyloides venezuelensis abrogated cDC1 presentation of dietary antigens, preventing pTreg and oral tolerance induction. In contrast, Heligmosomoides polygyrus infection only partially affected cDC1s, allowing oral tolerance to be maintained. An expanded population of cDC2s that induced type-2 immunity during both helminth infections did not present dietary antigens, demonstrating that compartmentalized presentation of luminal antigens can prevent food-specific Th2 responses during inflammatory conditions. Our data uncover novel cellular mechanisms by which tolerance to food is induced and can be disrupted during infections.

immunology↗

bioRxiv2018

Compartmentalized lymph node drainage dictates intestinal adaptive immune responses

The intestinal immune system has the challenging task of tolerating foreign nutrients and the commensal microbiome, while excluding or eliminating ingested pathogens. Failure in such balance leads to a range of severe intestinal and systemic diseases such as inflammatory bowel diseases, food allergies or invasive gastrointestinal infections1,2. Multiple innate and adaptive immune mechanisms are therefore in place to maintain tissue integrity, including efficient peripheral generation of effector T (TH) cells and FOXP3+ regulatory T (pTreg) cells, which mediate resistance to pathogens and regulate excessive immune activation, respectively2-5. The gut-draining mesenteric lymph nodes (mLNs) are critical sites for orchestrating adaptive immunity to luminal perturbations6-8. However, how they manage to simultaneously support tolerogenic and inflammatory reactions is incompletely understood. Here we report that individual mLNs are anatomically and immunologically distinct according to the functional gut segment they drain. Dendritic cell gene signatures and adaptive T cell polarization against the same luminal antigen differed between mLNs along the intestine, the proximal small intestine-draining mLNs preferentially giving rise to tolerogenic and the distal mLNs to pro-inflammatory T cell responses. This compartmentalized dichotomy could be perturbed by duodenal infection, surgical removal of select distal mLNs, dysbiosis, or ectopic antigen delivery, impacting both lymphoid organ and tissue immune responses. Our findings reveal that the conflict between tolerogenic and inflammatory adaptive responses is in part resolved by discrete mLN drainage, and encourage gut segment-specific antigen targeting for therapeutic immune modulation.

immunology↗