Objective
Our overall objective is to better understand how human T cells interact with pancreatic islet cells to drive T1D progression and pathogenesis.
Background Rationale
Type 1 diabetes (T1D) is thought to be driven in part by T lymphocytes, cells of the immune system responsible for fighting viruses and cancer. From mouse models of T1D, T cells are found directly in pancreatic islets and in lymph nodes that drain from the pancreas, and these T cells have been shown to directly drive T1D pathogenesis. Understanding how the mouse model of T1D relates to human T1D is challenging because getting T cells directly from the human pancreas or pancreas draining lymph nodes can only be done using deceased organ donor samples. Because of this, T1D-causing T cells in humans are mostly studied from the blood. These studies however typically involve artificial strategies to activate and expand the T cells which changes their biology. Human islet and pancreas draining lymph node T1D-causing T cells have been studied in rare cases, but again has required artificial systems to expand the cells, which again changes their biology. Most importantly, these human studies have not directly studied the interaction between pancreatic islet cells and T1D-causing T cells- the centrally most important aspect of T cell biology in T1D to understand. Our laboratory has developed a straightforward and novel co-culture strategy to study the direct interaction between T cells and individual islet cells for the first time, which is made possible by our access to human organ donor samples from Type-1 diabetics and Type-1 diabetic predisposed children and adults in the Human Pancreas Analysis Program. Our approach is also unique because we have developed a new way to isolate individual pancreatic islet cells while preserving their ability to interact with T cells. This co-culture method will be used to directly understand how human T1D-causing T cells recognize and respond to pancreatic islet cells, as well as how the islet cells respond to T cells trying to kill them.
Description of Project
Type 1 diabetes (T1D) is thought to be driven in part by T lymphocytes, cells of the immune system responsible for fighting viruses and cancer. From mouse models of T1D, T cells are found directly in pancreatic islets and in lymph nodes that drain from the pancreas, and these T cells have been shown to directly drive T1D pathogenesis. Understanding how the mouse model of T1D relates to human T1D is challenging because getting T cells directly from the human pancreas or pancreas draining lymph nodes can only be done using deceased organ donor samples. Because of this, T1D-causing T cells in humans are mostly studied from the blood. These studies however typically involve artificial strategies to activate and expand the T cells which changes their biology. Human islet and pancreas draining lymph node T1D-causing T cells have been studied in rare cases, but again has required artificial systems to expand the cells, which again changes their biology. Most importantly, these human studies have not directly studied the interaction between pancreatic islet cells and T1D-causing T cells- the centrally most important aspect of T cell biology in T1D to understand. Our laboratory has developed a straightforward and novel co-culture strategy to study the direct interaction between T cells and individual islet cells for the first time, which is made possible by our access to human organ donor samples from Type-1 diabetics and Type-1 diabetic predisposed children and adults in the Human Pancreas Analysis Program. Our approach is also unique because we have developed a new way to isolate individual pancreatic islet cells while preserving their ability to interact with T cells. This co-culture method will be used to directly understand how human T1D-causing T cells recognize and respond to pancreatic islet cells, as well as how the islet cells respond to T cells trying to kill them. Our studies will directly study the interaction of human T cells, known to cause Type-1 diabetes, with individual pancreatic islet cells, using cells and tissue obtained from individual either predisposed to Type-1 diabetes or those with early Type-1 diabetes. Importantly, we will study T cells from lymph nodes that drain the pancreas, a location known to contain T cells that were recently in the pancreas. Our studies will therefore allow us to understand how these T cells interact with islet cells to cause their destruction, potentially revealing novel pathways and mechanisms that could be targeted for drug development.
Anticipated Outcome
We anticipate that these studies will reveal which type of T cells interact with pancreatic islet cells to cause Type-1 diabetes, and how they do it. We also anticipate that we will learn how pancreatic islet cells respond to being targeted by T cells.
Relevance to T1D
Our studies will directly study the interaction of human T cells, known to cause Type-1 diabetes, with individual pancreatic islet cells, using cells and tissue obtained from individual either predisposed to Type-1 diabetes or those with early Type-1 diabetes. Importantly, we will study T cells from lymph nodes that drain the pancreas, a location known to contain T cells that were recently in the pancreas. Our studies will therefore allow us to understand how these T cells interact with islet cells to cause their destruction, potentially revealing novel pathways and mechanisms that could be targeted for drug development.