New discovery reveals pancreas’s immune tolerance allies
Researchers at Scripps Research have identified a previously unrecognized cell type in the pancreas—vascular-associated fibroblastic cells (VAFs)—that appear to actively protect insulin-producing cells from autoimmune attack. Published in Cell Reports on September 23, 2025, the study describes how VAFs help maintain immune tolerance in the pancreas, shedding new light on why type 1 diabetes can have a prolonged preclinical phase and offering a potential route to prevention or reversal of the disease.
What are VAFs and what do they do?
VAFs are specialized cells associated with the pancreas’s blood vessels. The Scripps team used advanced imaging, cell-labeling, and single-cell analysis to map how these cells participate in antigen presentation and immune signaling. In healthy tissue, VAFs present pancreatic fragments to immune cells in a way that calms potential autoimmune responses, creating a tolerant state known as anergy. This peacekeeping role helps shield insulin-producing beta cells from destructive immune activity.
Key mechanics: how VAFs mediate tolerance
During immune surveillance, cells display fragments of proteins to help determine if an immune response is warranted. VAFs contribute to this process by presenting pancreas-derived pieces while also sending signals that dampen immune activation. In effect, they act as local moderators, balancing the need to detect threats with the necessity of protecting insulin-secreting cells.
Why this matters for type 1 diabetes
Type 1 diabetes arises when the immune system targets insulin-producing beta cells, compromising blood sugar regulation. The discovery of VAFs helps explain several enigmatic features of the disease, including its lengthy preclinical phase where autoimmunity is underway but blood sugar remains normal. If VAFs fail or become overwhelmed by persistent inflammation—from infection, toxins, or environmental factors—the pancreas loses its tolerance and autoimmune attack accelerates.
Inflammation as a driver of dysfunction
The researchers found that ongoing pancreatic inflammation can overwhelm VAFs, triggering the immune system to shift into an autoimmune mode. This shift helps account for how environmental and physiological triggers may initiate or accelerate type 1 diabetes in susceptible individuals. The work reframes the problem from a sole focus on the immune system’s misbehavior to understanding how the pancreas maintains its own tolerance under stress.
Towards therapies that strengthen the body’s own defenses
The study points toward strategies that could bolster VAF functions, enhance states of anergy, or reduce inflammatory burdens in the pancreas. Such approaches would aim to preserve or restore the tolerance that keeps insulin production safe, rather than broadly suppressing immune activity. In the long term, therapies could be personalized to support a patient’s own vascular-associated fibroblastic cells, offering a targeted path to prevent or delay type 1 diabetes progression.
Broader implications and next steps
Beyond type 1 diabetes, the concept of tissue-resident tolerance mechanisms could inform autoimmune disease research and organ transplantation, where maintaining local immune balance is crucial. The Scripps team has secured additional funding—$3.2 million from the National Institute of Diabetes and Digestive and Kidney Diseases—to deepen the study of VAFs. By collaborating with other researchers, including Joseph Jardine, they aim to translate these insights into practical therapies that work with the body’s own protective systems.
A hopeful outlook for patients
For the 1.6 million Americans living with type 1 diabetes, the findings offer renewed optimism. If scientists can strengthen VAFs and sustain pancreatic tolerance, it may become possible to prevent autoimmunity from accelerating or to reverse early-stage disease by restoring the pancreas’s natural defense network.
About the researchers
Luc Teyton, a professor of Immunology and Microbiology at Scripps Research and senior author of the study, emphasizes a shift in perspective: the goal is not just to interrogate why the immune system attacks, but to understand what disrupts the pancreas’s tolerance and how to mend it. The team’s innovative use of FucoID, a labeling technique developed by Scripps Research’s Peng Wu, allowed rapid identification and isolation of key cells involved in this tolerance network.
