What disrupts the pancreas' natural ability to maintain tolerance?
Within the pancreas, a quiet civil war has long preceded the diagnosis of type 1 diabetes — and science is only now meeting the peacekeepers. Researchers at Scripps Research have identified a previously unknown class of cells, called vascular-associated fibroblastic cells, that appear to hold the immune system's aggression in check, protecting insulin-producing cells from destruction. Their discovery reframes the disease not as a simple failure of immune recognition, but as the collapse of a natural tolerance system — and in that reframing, a new possibility emerges: that the war might be prevented before it begins.
- 1.6 million Americans manage type 1 diabetes through daily injections and constant vigilance, living with the consequences of an immune system that has already won a battle the body never wanted to fight.
- Scientists have discovered that the pancreas possesses its own peacekeeping cells — VAFs — whose exhaustion under chronic inflammation may be the true trigger that unleashes autoimmune destruction.
- The disease's long symptom-free preclinical phase, once a mystery, now looks like a window: a period when VAFs are still fighting, and when early intervention might still prevent irreversible harm.
- Rather than broadly silencing the immune system, future therapies could target VAFs directly — reinforcing the body's own tolerance mechanisms and reducing the risks that come with systemic immune suppression.
- The implications reach beyond diabetes, touching organ transplantation and other autoimmune conditions where the body's capacity for tolerance is equally fragile and equally consequential.
Type 1 diabetes begins as a civil war inside the body — the immune system turning against the very cells that produce insulin, leaving 1.6 million Americans to manage blood sugar through daily injections, constant monitoring, and the ever-present risk of a dangerous miscalculation.
Scientists at Scripps Research have now identified a previously unknown participant in this conflict. Published in Cell Reports, the study describes vascular-associated fibroblastic cells, or VAFs — molecular peacekeepers in the pancreas that actively shield insulin-producing cells from immune attack. Senior author Luc Teyton suggests that understanding how VAFs work could eventually allow researchers to prevent or even reverse the disease. The discovery also sheds light on type 1 diabetes's puzzling preclinical phase, during which immune destruction is already underway yet blood sugar remains normal — a window that may be exploitable for early intervention.
To find VAFs, Teyton's team looked not at immune cells but at the pancreas itself, focusing on blood vessels known to be sites of inflammation. Using a cell-labeling technique called FucoID, they isolated cells performing multiple protective functions at once: presenting antigens to guide immune decisions and releasing chemical signals that induce tolerance, quieting immune cells before they can attack.
The pancreas is uniquely exposed to inflammatory triggers from digestion, toxins, and infection. VAFs normally manage this exposure — but under sustained inflammation, they become exhausted, their defenses collapse, and the autoimmune cascade begins. First author Don Clarke argues that the field should shift its focus from why the immune system attacks to what disrupts the pancreas's tolerance mechanisms, and how to restore them.
The team plans to develop therapies that strengthen VAFs rather than broadly suppress immunity — a more targeted approach that works with the body's own systems. The implications extend to other autoimmune diseases and organ transplantation, where tolerance is equally fragile. For those at risk of type 1 diabetes, this discovery marks a fundamental shift in how the disease might one day be stopped before it starts.
Type 1 diabetes begins as a civil war inside the body. The immune system, tasked with defending against genuine threats, instead turns on the cells that manufacture insulin—the hormone that keeps blood sugar in balance. For the 1.6 million Americans living with this condition, the result is a lifetime of careful arithmetic: multiple daily injections, constant blood sugar monitoring, dietary vigilance, and the ever-present risk that a miscalculation could become life-threatening.
Scientists at Scripps Research have now identified a previously unknown player in this conflict, one that may explain why the disease unfolds so slowly before symptoms appear. The discovery, published in Cell Reports, centers on a type of cell called vascular-associated fibroblastic cells, or VAFs. These cells function as what the researchers describe as molecular peacekeepers in the pancreas, actively shielding insulin-producing cells from immune destruction. The finding opens a new way of thinking about type 1 diabetes—not as a simple failure of the immune system to recognize friend from foe, but as a breakdown in the pancreas's natural ability to maintain tolerance.
Luc Teyton, a professor in the Department of Immunology and Microbiology at Scripps Research and senior author of the study, explains the significance: understanding how VAFs work could eventually allow researchers to prevent or even reverse the disease. The discovery also illuminates one of type 1 diabetes's most puzzling features—the long preclinical phase, a symptom-free period during which the immune system is already destroying insulin-producing cells, yet blood sugar remains normal. This gap between cellular damage and clinical symptoms suggests that early intervention might be possible before irreversible harm occurs.
To find VAFs, Teyton's team took an unconventional path. Rather than studying immune cells directly, they focused on the pancreas itself, zeroing in on post-capillary venules—blood vessels known to be sites of inflammation. Using a cell-labeling technique called FucoID, developed by Scripps Research professor Peng Wu, they identified and isolated the cells they were seeking. What emerged was a picture of VAFs performing multiple protective functions simultaneously. These cells participate in antigen presentation, a process in which cells display protein fragments to help the immune system decide whether to mount a response. But VAFs do more than simply present information—they also send chemical signals that calm the immune system, inducing a state called anergy, in which immune cells become tolerant and stop attacking.
The pancreas faces particular immunological challenges. As part of the digestive system, it is constantly exposed to inflammatory triggers from food, environmental toxins, and infections. Under normal circumstances, VAFs manage this exposure, maintaining a protective balance. But when inflammation becomes persistent and overwhelming, the system breaks down. VAFs become exhausted, their protective capacity collapses, and the immune system activates against insulin-producing cells. Once this autoimmune cascade begins, it perpetuates itself, destroying the very cells the body needs to regulate blood sugar.
Don Clarke, a former postdoctoral researcher at Scripps and first author of the study, reframes the question that researchers should now be asking: rather than focusing solely on why the immune system attacks, the field should ask what disrupts the pancreas's natural tolerance mechanisms, and crucially, how to restore them. This shift in perspective suggests a fundamentally different approach to treatment. Instead of broadly suppressing the immune system—a strategy that leaves patients vulnerable to infection and other complications—future therapies could work with the body's own protective systems, strengthening VAFs' ability to maintain tolerance or protecting them from being overwhelmed by inflammation.
The team, working with Scripps Research Assistant Professor Joseph Jardine, plans to deepen their understanding of VAFs and develop therapeutic strategies that enhance their protective functions. The goal is to create personalized treatments that prevent type 1 diabetes by reinforcing the body's tolerance mechanisms rather than fighting the immune system itself. The implications extend beyond type 1 diabetes; similar tolerance mechanisms may operate in other autoimmune diseases and in organ transplantation, where the body must learn to accept foreign tissue without attacking it. For millions of people at risk for type 1 diabetes, this discovery represents a fundamental shift in how the disease might one day be prevented or reversed.
Notable Quotes
Rather than just asking why the immune system attacks, we can now ask: what disrupts the pancreas' natural ability to maintain tolerance? And more importantly, how can we restore it?— Don Clarke, former postdoctoral researcher at Scripps Research and first author of the study
This discovery unlocks a new understanding of autoimmunity and could help us design better therapeutics for type 1 diabetes and inform how we prevent or reverse the disease.— Luc Teyton, professor in the Department of Immunology and Microbiology at Scripps Research
The Hearth Conversation Another angle on the story
So these VAF cells are essentially peacekeepers. But what happens when they fail? Is it a sudden collapse or a slow erosion?
It's more like a system being overwhelmed. The pancreas is constantly exposed to inflammatory triggers—food particles, environmental toxins, infections. VAFs normally manage this, but when inflammation becomes persistent and intense, they exhaust. They can't keep sending the calming signals anymore.
And once they fail, the immune system just... turns?
Yes. Once VAFs lose their grip, the immune system activates against insulin-producing cells. But here's what's interesting—this happens during that long preclinical phase when blood sugar is still normal. The damage is already occurring, but the body hasn't yet lost enough insulin-producing capacity to show symptoms.
That's why early intervention could work.
Exactly. If you could identify and strengthen VAFs before they become overwhelmed, you might prevent the cascade entirely. You're not fighting the immune system; you're reinforcing the body's own protective system.
So the therapy wouldn't be immunosuppression.
No. That's the crucial shift. Immunosuppression leaves you vulnerable to infections and other problems. This approach works with the body's natural tolerance mechanisms. You're asking: how do we help VAFs do their job better?
What made the researchers think to look at VAFs in the first place?
They focused on the pancreas itself rather than immune cells. They looked at blood vessels known to be inflammation sites and used a specialized cell-labeling technique to identify what was actually there. It was a different angle entirely.