Objective
The main goal of this project is to explore whether manipulating T cell metabolism can help delay or prevent the destruction of insulin-producing beta cells in type 1 diabetes (T1D) by autoimmune T cells. Our recent findings demonstrate that blocking monocarboxylate transporte 1 (MCT1) reduces T cell metabolism and promotes specific T cell unresponsiveness. Therefore, we will use specific pharmacological MCT1 inhibitors to treat non-obese diabetic mice and will generate a genetically modified mouse model with specific deletion of MCT1 in T cells to assess its role in disease progression.
Background Rationale
In type 1 diabetes (T1D) the immune system attacks the insulin-producing beta cells in the pancreas and T cells are the main drivers of this destruction. Because of this, scientists are looking for ways to specifically control T cell autoimmunity that could be used as treatment for the disease. Recent research has shown that changing how T cells use energy can either boost or suppress their ability to attack other cells. This approach is already being explored for new treatments in cancer and autoimmune diseases, but its role in T1D is not yet well understood. This novel project aims to reduce the immune attack on insulin-producing beta cells by blocking a protein called monocarboxylate transporter 1 (MCT1) on T cells. MCT1 helps T cells remove lactate, a waste product from their energy use, which can inhibit their function. By inhibiting MCT1, we hope to modify the specifically harmful T cell response against the beta cells and slow or prevent the progression of T1D.
Description of Project
Type 1 diabetes (T1D) is an autoimmune disease in which the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas, leading to hyperglycemia. While insulin therapy is an essential treatment, it does not fully restore normal blood sugar regulation, and people with T1D still face reduced life expectancy and a lower quality of life. Significant progress has been made in beta cell replacement therapies, including islet transplantation and stem cell-based approaches. However, despite advancements in understanding how immune cells contribute to beta cell destruction, there are still no effective treatments to fully prevent this autoimmune attack. In T1D, T cells play a central role in beta cell destruction. These cells undergo metabolic changes, relying on glycolysis, a process that breaks down sugar to generate energy, to sustain their attack. This process leads to the accumulation of lactate, a metabolic byproduct that can alter T cell function. Our recent findings in viral infection models demonstrated that a protein called monocarboxylate transporter 1 (MCT1) helps T cells remove excess lactate produced during glycolysis. Interestingly, when MCT1 is blocked, T cells become less active and enter a state of exhaustion, losing their ability to kill. Based on these findings, we hypothesize that inhibiting MCT1 in T cells could prevent or delay T1D progression by dampening their destructive activity. In this project, we will test this hypothesis using both genetic and pharmacological approaches to block MCT1 in T cells in a well-established mouse model of T1D, the non-obese diabetic (NOD) mouse. These innovative experiments will provide valuable insights into the role of T cell metabolism in T1D and may pave the way for novel therapies to protect beta cells, ultimately improving disease management and offering hope for prevention.
Anticipated Outcome
The results of this project will fill a major gap in type 1 diabetes (T1D) research by clarifying the role of T cell metabolism in the development of the disease. In addition, it could identify a new therapeutical target for T1D.
Relevance to T1D
Current immunotherapies for type 1 diabetes (T1D) aim to block harmful immune responses, but they often require continuous use or cause unwanted side effects, such as weakened immunity. This can increase the risk of infections, particularly in children. Our project is exploring a different strategy: targeting MCT1 to regulate T cell activity in T1D. MCT1 is primarily required by rapidly dividing cells, such as activated T cells and tumor cells. Blocking it could reduce harmful immune responses without causing widespread immune suppression or serious side effects like those seen with other therapies. Cancer studies suggest that MCT1 inhibitors do not cause significant adverse effects in mice. Since these inhibitors are already being tested in early-stage clinical trials for some cancers, they could also become promising new treatments for T1D.