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Principal Investigator: Daria Esterhazy
Organization: UNIVERSITY OF CHICAGO
Fiscal Year: 2024
Award: $340,096
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Abscission><Address><Affect><Ailmentary System><Alimentary System><Anatomic Sites><Anatomic structures><Anatomy><Antigen Presentation><Antigens><Attention><Autoimmune Diabetes><Automobile Driving><Autoregulation><B9 endocrine pancreas><Back><Beta Cell><Biotin><Biotinylation><Body Tissues><Brittle Diabetes Mellitus><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Clone Cells><Cre driver><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><D-Glucose><Dendritic Cells><Development><Dextrose><Diabetes Mellitus><Diet><Digestive Diseases><Digestive System><Digestive System Diseases><Digestive System Disorders><Disease><Disease Progression><Disorder><Dorsum><Drainage><Drainage procedure><Duodenum><Dysfunction><Endocrine Pancreas><Endocrine Pancreas Secretion><Environment><Enzyme Gene><Enzymes><Evolution><Excision><Exhibits><Exocrine Pancreas Secretion><Exocrine pancreas><Exposure to><Expression Signature><Extirpation><Failure><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><GI tract disorder><Gastrointestinal Body System><Gastrointestinal Organ System><Gene Expression Profile><Gene Transcription><Genetic Transcription><Glucose><Goals><Hepatic><Homeostasis><Homing><Hormone secretion><Humulin R><IDDM><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune Targeting><Immune response><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Infection><Inflammatory><Injury><Insulin><Insulin Cell><Insulin Secreting Cell><Insulin-Dependent Diabetes Mellitus><Intestinal><Intestines><Islands of Langerhans><Islets of Langerhans><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Life><Ligase><Ligase Gene><Liver><Liver Extract><Location><Lycopersicon esculentum><Lymph><Lymph Node Drainage><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Malignant Pancreatic Neoplasm><Malignant neoplasm of pancreas><Mediating><Methods><Mice><Mice Mammals><Modeling><Monitor><Murine><Mus><Nature><Nesidioblasts><Novolin R><Nutrient><Organ><Outcome><Output><Pancreas><Pancreas Cancer><Pancreatic><Pancreatic Cancer><Pancreatic Diseases><Pancreatic Disorder><Pancreatic Endocrine Secretion><Pancreatic Exocrine Secretion><Pancreatic Islets><Pancreatic beta Cell><Pancreatic β-Cell><Pancreatitis><Pars endocrina pancreatis><Phenotype><Physiological Homeostasis><Physiopathology><Positive Lymph Node><Predisposition><Proteins><RNA Expression><Reaction><Regular Insulin><Regulation><Removal><Research><Route><Shapes><Site><Solanum lycopersicum><Source><Structure of beta Cell of islet><Sudden-Onset Diabetes Mellitus><Surgical Removal><Susceptibility><Synthetases><System><T cell response><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><T8 Cells><T8 Lymphocytes><Testing><Therapeutic Intervention><Tissues><Tomatoes><Toxin><Transcription><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><Veiled Cells><Vitamin H><adaptive immunity><autoimmune reactivity><autoreactive T cell><autoreactivity><bowel><cellular targeting><coenzyme R><cytotoxic><developmental><diabetes><diets><digestive disorder><digestive tract disease><draining lymph node><driving><enteral infection><enteric infection><enteric pathogen infection><enteropathogen infection><enteropathogenic infection><exocrine pancreatic><flow cytophotometry><gastrointestinal system><gastrointestinal tract disease><gastrointestinal tract disorder><gene expression pattern><gene expression signature><hepatic body system><hepatic organ system><hormonal secretion><host response><immune system response><immunogen><immunological status><immunoresponse><imprint><infected with enteropathogen><injuries><insight><insulin dependent diabetes><insulin dependent type 1><intervention therapy><intestinal infection><intestine infection><islet progenitor><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><killer T cell><lymph gland><lymph nodes><lymph organ><lymphatic fluid><lymphatic organ><lymphnodes><lymphoid organ><macromolecule><man><node positive><novel><pancreas beta cell><pancreas disorder><pancreas β cell><pancreatic b-cell><pancreatic malignancy><pathophysiology><polarized cell><prevent><preventing><regional lymph node><resection><response><self-reactive T cell><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><transcriptional profile><transcriptional signature><type I diabetes><type one diabetes><uptake><virtual><β-cell><β-cells><βCell>