Luc Teyton, professor in the Department of Immunology and Microbiology at Scripps Research, has received a five-year, $3.2 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to help answer how type 1 diabetes manifests and develop potential therapeutics to reverse or prevent the disease.
Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks the cells that produce insulin-a critical hormone that regulates the blood sugar of the body. Approximately 1.6 million Americans live with type 1 diabetes, and while genetics play a strong role in susceptibility, scientists still don't fully understand what initiates the autoimmune attack.
Collaborating with Assistant Professor Joseph Jardine, Teyton aims to understand how type 1 diabetes emerges by studying vascular-associated fibroblastic cells (VAFs). Although rare, VAFs act as molecular peacekeepers in the pancreas-actively protecting insulin-producing cells from the immune system. Early research from Teyton and his lab suggests that type 1 diabetes may manifest when VAFs become overwhelmed, forcing the immune system to activate and destroy the valuable insulin-producing cells that balance the body's blood sugar levels.
Type 1 diabetes significantly impacts the lives of patients and their families, and despite decades of efforts to understand it, the inner workings of the disease are still a mystery. Discovering VAFs is just the tip of the iceberg. In the next phase of our research, we will use this funding to further explore how we might strengthen these cells in the face of inflammation-potentially finding avenues to a cure."
Luc Teyton, Professor, Department of Immunology and Microbiology, Scripps Research
Teyton's grant builds on a discovery his team published in Cell Reports in September 2025. Working with both mouse models and human pancreatic tissue, the researchers identified VAFs clustered around the insulin-producing regions of the pancreas. These cells were doing something unexpected: presenting pancreatic antigens-fragments of proteins-to the immune system.
Under normal circumstances, only specialized immune cells have the molecular machinery to present antigens, which alert the immune system to potential threats. Surprisingly, VAFs also express these molecules and display pancreatic components to passing immune cells. However, VAFs simultaneously express PD-L1, molecule that delivers inhibitory "don't attack" signals, creating a protective, balanced environment. When persistent inflammation occurs, VAFs dramatically increase their antigen presentation while their protective inhibitory signals remain constant. This imbalance-heightened alarm signals without proportional "all clear" signals-may inadvertently trigger the immune system to activate and destroy insulin-producing cells.
This finding challenged the conventional view of type 1 diabetes. Scientists had long assumed the disease began when immune cells infiltrated pancreatic islets-the clusters that contain insulin-producing cells-and attacked them directly. But when Teyton's team examined tissue from mice and humans, they found immune cells gathered exclusively outside the islets, not within them. The VAFs sat right at this boundary, positioned between the pancreatic islets and the blood vessels.
"We've been looking in the wrong place," adds Teyton. "For years, we assumed type 1 diabetes began inside the pancreatic islets. But our research suggests the real action is happening on the outside-in cells that shouldn't be presenting pancreatic antigens to the immune system at all."
Now, the new NIDDK grant will allow Teyton's laboratory to dig deeper into these findings. The team will create a comprehensive analysis of all antigen-presenting cells in normal and pre-diabetic pancreatic islets. Using advanced techniques, they'll track how these cell populations change as the disease develops.
The team will also investigate why VAFs present only fragments of peptides, rather than traditional antigen-presenting immune cells that display whole proteins. Understanding more about this process could reveal specific targets for therapeutic intervention.
Unlocking how inflammation disrupts healthy function of the pancreas is also key. While inflammatory molecules have long been known to induce antigen presentation, recent evidence points to alternative pathways involving diet and gut-derived factors. The researchers will test various inflammatory signals in mice to understand what causes VAFs to shift from protective peacekeepers to potential troublemakers.
"We hypothesize that communication between the gut and pancreas may drive the local inflammation that overwhelms VAFs," says Teyton. "Understanding these triggers could reveal entirely new intervention points."
This grant will include research efforts as outlined in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant #1UG3DK142188-01 which will employ models to study the initiation and progression of type 1 diabetes.
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