# Immune crosstalk through shared LN drainage in the digestive system

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2023 · $354,267

## Abstract

PROJECT SUMMARY/ABSTRACT
Hypothesis: Diseases of the pancreas are life-threatening, including pancreatic cancer (PDAC), affecting
exocrine cells, and autoimmune diabetes (T1D), destroying insulin-producing β cells. External factors like
infections and diet are implicated as triggers, but the disease origins remain elusive and cures are lacking. The
immune system strongly contributes to disease progression, but what governs pancreatic adaptive immune
tone is understudied, preventing effective immune-targeting therapy. Lymph nodes (LNs) are key sites for the
initiation of tissue specific adaptive immunity, and here we hypothesize that LN sharing between pancreas
and duodenum and liver influences the nature of pancreatic immunity. We postulate that both, the major
lymph output from these co-drained organs and their more direct exposure to environmental perturbation, allow
them to dictate LN environments, thus impacting pancreatic adaptive immune cell fate both during homeostasis
and upon intestinal or hepatic insults. Finally, we propose that migratory dendritic cells (DCs) presenting
pancreatic antigen are the key cellular target for such immune cross talk.
This hypothesis will be tested in our Specific Aims (SA): SA #1 will characterize the phenotype of
pancreatic antigen loaded DC and consequences for exocrine or endocrine pancreas specific T cell
polarization in the co-drained LNs during homeostasis. SA #2 will test to what extent LN DCs and T cell
fates change upon intestinal versus hepatic perturbation such as infections. SA #3 will assess the relative
importance of sharing LNs with liver versus gut for the T cell landscape back in the exocrine and endocrine
pancreatic tissue and, as a proof of principle, will investigate how duodenal infection, through LN sharing,
affects pancreatic tissue T cells and the progression of T1D.
Unique approach: 1. We will identify LN DCs loaded with pancreatic antigen by virtue of tracking tissue specific
antigen biotinylation or fluorescent protein uptake. 2. We have generated novel mice that permit expression of
the model antigen OVA from exocrine or endocrine pancreas, liver or gut, allowing for monitoring OVA specific
T cell fate. This method permits the systematic comparison of tissue-specific T cell responses in the LNs
shared with the liver versus the duodenum.
Impact: This project will provide fundamental insights into how pancreatic immunity may be shaped by
environmental fluctuations. While potential sources of pancreatic perturbation through LN sharing, liver and
duodenum could turn out as anatomical routes for therapeutic intervention in the pancreas. Mechanistically the
research will increase our understanding of DC imprinting in tissue versus LN and the impact of this “plasticity”
on dictating T cell responses. More broadly, the proposal features LN sharing between organs as a previously
unrecognized force shaping tissue specific immunity.

## Key facts

- **NIH application ID:** 10652641
- **Project number:** 5R01DK133393-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Daria Esterhazy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $354,267
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652641

## Citation

> US National Institutes of Health, RePORTER application 10652641, Immune crosstalk through shared LN drainage in the digestive system (5R01DK133393-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10652641. Licensed CC0.

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