Objective
One of the body’s best tools for preventing immune attack against the insulin-producing beta cells of the pancreas lies in a special group of immune cells called regulatory T cells, or Tregs. These cells are the guardians of our organs and prevent other immune cells from attacking our body’s own tissues. When Tregs work properly, they help prevent autoimmune diseases like T1D. Unfortunately, in people with T1D, this system of checks and balances breaks down. Either Tregs don’t show up in the right place at the right time, or they don’t have the tools they need to stop the attack on the pancreas.
Many researchers are now developing therapies that use Tregs to restore balance to the immune system to prevent or reverse T1D. But there’s a major challenge – most of the Tregs used in these treatments are generic and are not specially trained to recognize the pancreas. As a result, they don’t always know where to go or how to focus their efforts on stopping the immune cells that are causing the damage. For Treg therapy to be truly effective, we need Tregs that are trained specifically to recognize and protect the pancreas.
The goal of this research is to unlock the body’s natural blueprint for immune tolerance by studying a unique group of Tregs that are created early in life, known as neonatal regulatory T cells. During a baby’s first weeks of life, the thymus (an organ that trains immune cells) produces a powerful set of Tregs designed to protect the body from attacking itself. These early Tregs are better at their job, longer-lasting, and more stable than Tregs produced later in life. Animal studies have already shown that if you remove neonatal Tregs, autoimmune diseases like T1D develop more quickly. On the flip side, giving neonatal Tregs to animals at risk of T1D can prevent the disease from developing. Despite their exciting potential, we don’t yet fully understand how neonatal Tregs learn to recognize the pancreas, or what specific proteins in the pancreas they are trained to target. Without that knowledge, we are unable to create effective, pancreas-specific Treg therapies for people living with T1D.
This research will focus on answering three major questions:
1. What proteins from the pancreas are presented in the thymus to help “train” neonatal Tregs? We will map these proteins in detail, both in laboratory mice and in human samples, to identify which parts of the pancreas the immune system is exposed to early in life.
2. What are the genetic instructions (T cell receptors, or TCRs) that neonatal Tregs use to recognize these pancreatic proteins? We will isolate and study these TCRs, identifying the most promising ones for therapeutic use.
3. Can we use this knowledge to engineer Tregs that specifically target the pancreas and stop the immune attack in T1D? By inserting these TCRs into Tregs, we hope to develop therapies that travel directly to the pancreas, turn off the autoimmune attack, and preserve the insulin-producing cells.
By answering these questions, this project aims to provide a foundation for creating precision Treg therapies that could prevent or even reverse T1D. These therapies could work alone or alongside other treatments like beta-cell replacement to offer people with T1D a real, lasting cure.
Background Rationale
Type 1 diabetes (T1D) is an autoimmune disease caused by a breakdown in the body’s ability to distinguish between its own tissues and harmful invaders like bacteria or viruses. In T1D, certain immune cells called T cells mistakenly attack the insulin-producing cells in the pancreas, eventually leading to complete loss of insulin and lifelong dependence on insulin injections or pumps. Under normal conditions, the immune system has built-in safeguards to prevent this from happening. These safeguards include a special group of immune cells called regulatory T cells, or Tregs, which make sure the immune system doesn’t attack the body’s own tissues. In animal models, removing Tregs causes rapid onset of diabetes. In people, rare genetic disorders that affect Tregs often lead to early, severe autoimmune diseases, including T1D. Even in healthy individuals, Tregs are found inside the pancreas, helping to maintain balance. Unfortunately, in T1D, Tregs either don’t work properly or are present in too few numbers to prevent the attack on the pancreas.
So what can we do about it? One promising area of research is developing therapies that use Tregs to restore immune balance in T1D. The idea is that by giving a person Tregs that have been engineered to recognize the pancreas better, we can stop the immune attack before it’s too late. So far, most clinical studies have used general-purpose (polyclonal) Tregs, which aren’t specifically directed to the pancreas. However, Tregs that are trained to recognize the pancreas specifically are thought to be much more effective because they can travel directly to the pancreas and focus their suppressive power exactly where it’s needed.
This is where neonatal Tregs – Tregs formed during the newborn period – come into focus. These early-life Tregs are specially selected in the thymus to recognize self-proteins, including those found in the pancreas. Studies in mice show that neonatal Tregs are especially good at preventing autoimmune diseases, including T1D. They last longer, function better, and are more stable than Tregs generated later in life. Despite their potential, we still don’t fully understand which pancreatic proteins these neonatal Tregs recognize or how to harness their power to prevent T1D in humans.
Our research seeks to solve that problem by identifying the specific proteins in the pancreas that neonatal Tregs are trained to recognize and by isolating the genetic “instructions” (TCRs) that allow them to do so. By engineering new Tregs with these precise instructions, we aim to develop therapies that can not only stop the immune system from attacking the pancreas in the early stages of disease, preserving the body’s own insulin production, but also for individuals with advanced, end-stage T1D who have already lost all of their insulin-producing cells. In these cases, engineered Tregs could be used to protect transplanted beta-cells from immune attack, helping to make beta-cell replacement therapies a durable, long-term cure for T1D.
Description of Project
Type 1 diabetes is a lifelong autoimmune disease that occurs when the body’s own immune system mistakenly attacks and destroys the insulin-producing cells of the pancreas. Insulin is essential for controlling blood sugar levels, and without it, people with T1D must rely on daily insulin injections or pumps to survive. While these therapies can help manage the disease, they do not address the underlying cause whereby the immune system has lost its ability to recognize the pancreas as “self.” As a result, there is still no cure for T1D, and current treatments often lead to long-term complications such as vision loss, kidney disease, and cardiovascular problems.
One of the most promising strategies for addressing the root cause of T1D involves using a special type of immune cell called a regulatory T cell, or Treg. Tregs play a critical role in preventing autoimmunity by teaching the immune system to ignore the body’s own healthy tissues and to dampen inflammation when unwanted recognition occurs. When Tregs are functioning properly, they prevent the immune system from attacking vital organs, including the pancreas. Unfortunately, research has shown that in people with T1D, Tregs often don’t work as well as they should, contributing to the development of T1D. To fix this, researchers are trying to develop Treg-based therapies to help restore immune tolerance. However, many of these approaches rely on generic, broad-acting Tregs that are not specifically designed to target the pancreas. As a result, Treg therapies don’t always reach the right tissues, limiting their potential to cure disease.
My research focuses on redesigning and improving existing Treg therapies. In particular, we propose to study a special population of Tregs that are formed in the thymus during the newborn period, known as neonatal regulatory T cells. These cells are created early in life through a highly selective process in which their T cell receptors (TCRs) recognize proteins from the body’s own tissues (self-antigens) that are presented in the thymus. This process helps build a long-lasting immune system that knows how to distinguish between harmful invaders and the body’s own organs. In studies using animal models, neonatal Tregs have been shown to be particularly effective at preventing autoimmune diseases like T1D. Our goal is to understand the exact pancreatic proteins these neonatal Tregs recognize and test the therapeutic potential of pancreas-specific Tregs.
In this project, we aim to achieve these goals through two major research aims. First, we will identify the specific proteins from the pancreas that are presented in the thymus during early life and that help guide the formation of neonatal Tregs. Using cutting-edge technologies, we will create a comprehensive map of the pancreatic proteins available for immune “training” of Tregs. Second, we will isolate the genetic sequences of TCRs from these neonatal Tregs, focusing on those that recognize important pancreatic proteins like insulin. By engineering new Tregs that express these specific TCRs, we will create targeted therapies that can home directly to the pancreas and actively suppress the immune system’s attack on insulin-producing cells. We will test these engineered Tregs in preclinical models of T1D to determine their effectiveness in preventing or even reversing the disease.
By uncovering the pancreatic antigens that are responsible for generating suppressive, pancreas-homing Tregs, our goal is to lay the foundation for a new generation of precision Treg therapies for T1D. Ultimately, our goal is to develop a treatment that restores lasting immune tolerance, protects pancreatic cells, and makes future curative therapies – like beta-cell replacement – not only possible but durable.
Anticipated Outcome
The goal of this research is to discover and harness the natural mechanisms of immune tolerance that form early in life. By understanding how the body generates highly specialized immune cells called regulatory T cells (Tregs) during the newborn period, we can design better therapies to stop the progression of T1D - or even cure it. Specifically, we are focused on identifying the exact proteins in the pancreas that help train these protective Tregs and using that knowledge to create next-generation, pancreas-targeting Treg therapies.
If successful, this research will produce three major outcomes that have the potential to transform how we treat T1D:
1. Creation of a detailed map of pancreatic “self” proteins that help train protective immune cells early in life.
One of the most important discoveries we expect to make is a complete list of the proteins from the pancreas that are presented in the thymus during the newborn period. These proteins instruct developing immune cells, helping them learn to recognize the body’s own tissues and avoid attacking them. By using advanced laboratory techniques to study these proteins in both mice and humans, we will provide the first comprehensive view of the pancreatic “self-antigens” that are essential for establishing immune tolerance. This information will not only be valuable for T1D but could also help in understanding and preventing other autoimmune diseases in the future.
2. Identification of specific T cell receptors (TCRs) from neonatal Tregs that can recognize and protect the pancreas.
Tregs rely on unique molecular “sensors,” called T cell receptors (TCRs), to recognize specific tissues in the body. We anticipate identifying which TCRs are critical for recognition of pancreatic proteins. These TCRs will be invaluable for designing new types of precision therapies, allowing scientists to engineer Tregs that are naturally drawn to the pancreas. With these tools in hand, we can move beyond generic immune therapies toward personalized treatments that target the immune dysregulation that underlies T1D.
3. Development of engineered, pancreas-specific Treg therapies with the potential to prevent or reverse T1D.
Perhaps the most exciting outcome of this project is the creation of engineered Tregs that are tailored to recognize and suppress the immune attack on the pancreas. These precision Tregs will be tested in preclinical models to evaluate their ability to stop the autoimmune destruction of insulin-producing cells. By using Tregs equipped with pancreas-specific TCRs, we expect these therapies to provide long-lasting, targeted protection of the pancreas without weakening the immune system’s ability to fight infections elsewhere in the body. This targeted approach would also make it possible to combine Treg therapy with other promising strategies, such as transplanting new insulin-producing cells, to offer a truly durable treatment – or even a cure – for people with T1D.
In addition to these scientific breakthroughs, this project will generate valuable resources, such as antigen libraries and validated TCR sequences, that can accelerate other research efforts in T1D and autoimmunity. Ultimately, the anticipated outcome of this work is a clear path forward for creating precision, antigen-specific Treg therapies capable of restoring immune balance, protecting insulin-producing cells, and giving people with T1D the chance to live free from the burden of constant treatment.
Relevance to T1D
Type 1 diabetes (T1D) affects millions of children and adults worldwide, and its impact reaches far beyond the daily routines of checking blood sugar, injecting insulin, and counting carbohydrates. T1D is not just an inconvenience, it is a life-altering, lifelong condition that carries serious risks of complications like heart disease, kidney failure, nerve damage, and vision loss. Despite enormous advances in insulin therapies and glucose monitoring, the harsh reality is that none of these treatments actually cure the disease. They only manage the symptoms while the immune system continues its attack on the pancreas. To truly change the future for people with T1D, we need therapies that don’t just manage the disease; we need therapies that can stop the underlying cause. That is the focus of this research.
T1D is caused by a breakdown in what scientists call immune tolerance – the body’s ability to recognize its own tissues and protect them from immune attack. Normally, a specialized type of immune cell called a regulatory T cell (or Treg) plays a key role in maintaining this tolerance. These cells act like immune system referees, making sure that other immune cells don’t accidentally attack healthy tissues like the pancreas. In people who develop T1D, this system breaks down. Either the Tregs are too few in number, they don’t work properly, or the immune system generates too many aggressive T cells that overwhelm the body’s defenses. The result is a slow, relentless destruction of the insulin-producing cells that people with T1D depend on to survive.
Right now, researchers around the world are working on ways to restore this lost tolerance, and Treg therapies are among the most promising strategies. Unfortunately, most of the Treg therapies being tested today are broad and non-specific. That means they try to calm down the immune system in general, without directly addressing the specific immune attack on the pancreas. While these treatments may help temporarily, they’re not enough to provide lasting protection, and they may even carry risks of unwanted side effects, like weakening the immune system too much in other parts of the body.
What makes this research different is that we are going straight to the source of natural immune tolerance - the thymus during early life, where the immune system learns what to fight and what to leave alone. By studying neonatal regulatory T cells, which are unique Tregs produced in the newborn period, we can uncover how the body naturally trains Tregs to recognize and protect the pancreas before autoimmune diseases like T1D can begin. Even more importantly, we are working to identify the exact pancreatic proteins that help train these cells, along with the specific genetic “instructions” (called T cell receptors, or TCRs) that allow them to find and protect the pancreas. This is like giving Tregs a GPS with the coordinates set for the pancreas, so they can go exactly where they’re needed and prevent the immune attack from continuing.
For people with T1D, the potential impact of this work is enormous. By developing precision-engineered Tregs that are trained specifically to stop the immune attack on insulin-producing cells, we can move closer to treatments that don’t just slow down the disease, but that halt or even reverse it. Coupled with other breakthroughs, like transplants of new insulin-producing cells, we are getting ever closer to creating a future where insulin therapy is no longer needed at all. We believe that this research offers hope for something that’s been missing in T1D care: not just better management, but a true path to immune correction, long-term protection, and lasting freedom from the disease.