Objective
see above "General Audience Summary"
Background Rationale
see above "General Audience Summary"
Description of Project
Specialized cells of the immune system, called T cells, survey the body, finding cells that have been infected by viruses or bacteria and killing them. Unfortunately, in some people, T cells turn against uninfected, normal cells in their body and destroy them, causing autoimmune disease. For over a century, scientists have tried to understand why in patients with autoimmune Type 1 diabetes, T cells destroy beta cells in the pancreas. Beta cells produce insulin, which is essential for regulating sugar levels and metabolism in the body, and without insulin, a patient will die. To answer why beta cell-specific T cells destroy beta cells and cause Type 1 diabetes, we used a mouse model called NOD, or non-obese diabetic. NOD mice develop Type 1 diabetes over time in a manner very similar to patients with Type 1 diabetes. In NOD mice, T cells specific for beta cells get activated and progressively destroy the cells over many months, causing the mouse’s blood sugar levels to rise until they are diabetic. We followed beta cell–specific T cells in NOD mice, over the lifespan of the mice, particularly in the pancreas and in specialized tissues called lymph nodes, which are the seedbed for developing T cells. We found that in pancreatic lymph nodes, a specialized subset of beta cell–specific T cells, which we called “autoimmune stem-like T cells,” constantly regenerate more beta cell–specific T cells which migrate to the pancreas and destroy beta cells. Strikingly, we showed that as few as 10 autoimmune stem-like T cells could be transferred into a healthy mouse, give rise to numerous progeny T cells, and cause diabetes. In this proposal we aim to understand the precise cellular and molecular features of autoimmune stem-like T cells in NOD mice and patients with Type 1 diabetes to identify novel therapeutic targets and strategies for the prevention and treatment of Type 1 diabetes.
Anticipated Outcome
see above "General Audience Summary"
Relevance to T1D
In the last few decades Type 1 Diabetes (T1D), like many autoimmune diseases, has increased in incidence for reasons that are incompletely understood. T1D pathogenesis is complex and involves immune infiltration of the pancreas and destruction of insulin-producing β-cells by β cell-specific CD8 T cells, leading to insulin deficiency and loss of glucose homeostasis. Patients with T1D require lifelong exogenous insulin replacement and often develop multi-organ dysfunction, increased morbidity and mortality, emphasizing the need to develop new strategies to prevent and treat T1D. Despite notable advances in our understanding of T1D causative antigens, many aspects remain enigmatic, including where and how the autoimmune β cell-specific CD8 T cell population arises and is sustained. To identify and design effective strategies for the prevention and treatment of T1D, we must understand the underlying mechanisms and factors that determine the development and maintenance of the autoimmune CD8 T cell state. This proposal employs clinically relevant mouse model of T1D as well as tissues from patients with T1D to define autoimmune T cell programs which could yield promising molecular and cellular targets for the prevention or treatment of T1D.