The training platform in this proposal examines how B lymphocytes disrupt Regulatory T Lymphocytes (Tregs) in Type 1 Diabetes (T1D). T1D is an incurable autoimmune disease with significant morbidity and mortality. Although cytotoxic T lymphocytes are directly responsible for the autoimmune destruction of pancreatic beta cells, Tregs fail to suppress this inappropriate immune response. The exact defect in Tregs that leads to failure to protect the pancreatic islet is unknown. During development from precursor T lymphocytes, nascent Tregs in the thymus are exposed to antigen by antigen-presenting cells, including thymic B lymphocytes. In my preliminary studies, I show that the presence of B lymphocytes leads to decreased protective islet-reactive Tregs in the mouse model of T1D, the NOD mouse. Our lab has also shown that a B lymphocyte deficient NOD mouse can be tolerized to islet transplant, and post-transplant, has increased numbers of Tregs. These studies indicate the important biologic impact of B lymphocytes on immune regulation in T1D and reveal that B lymphocytes are the critical barrier preventing inducible tolerance in T1D. I hypothesize that thymic B lymphocytes interfere with nave T cell development, such that both thymically-derived Tregs and nave T cells that might later go on to become peripherally-induced Tregs are unable to appropriately protect the islet. I will dissect the mechanism behind how B lymphocytes interfere with T cell development by using fetal thymic organ culture and mass cytometry to visualize direct effects of B lymphocytes on Tregs (Aim 1). I will evaluate the timing in which a B lymphocyte is able to permanently impact T cell development by using two-photon microscopy and transgenic antigen-specific mouse models to elucidate whether a T cell is forever changed by interaction with a thymic B lymphocyte (Aim 2). Through this fellowship application, I will demonstrate the mechanisms behind Treg dysregulation, which will allow for novel therapeutic strategies for patients with T1D. The endocrinology and immunology I learn as a graduate student underlies the research I will dedicate my career to: investigating Type 1 Diabetes and Systemic Lupus Erythematosus in pregnancy. In addition to the scientific training, I will also be supported by my newly formed career mentoring committee composed of experts in research relating to pregnancy and in the development of proceduralist-scientists. Through this integrated training program, I will develop a foundation for my development as a basic scientist that will serve me as I pursue a career as an obstetrician scientist.
Type 1 Diabetes, a lifelong autoimmune disease that will be diagnosed in more than 15,000 children this year, is characterized by autoimmune attack of pancreatic beta cells in the Islets of Langerhans. In NOD mice and patients with Type 1 Diabetes, Regulatory T lymphocytes fail to appropriately protect either native islets or islet transplants, which I propose relates to a newly uncovered role for B lymphocytes in Treg development and function. This proposal will train a new investigator to focus on Type 1 Diabetes and other autoimmune diseases by elucidating mechanisms to enhance Regulatory T lymphocyte function that could become important therapeutic options for patients.
