Our laboratory was the first to show that blockade of CD28 signals can prevent allograft rejection. Using new conditional CD28 knockout mice just generated in our lab and various Cre strains, we are examining the role of CD28 in Treg development, conversion, and survival, and its importance for maintaining established T effector driven immune respones, including transplantation, autoimmunity, and helper dependent antibody production. A second program is the role of the PI3 kinase pathway in regulatory T cells. The tumor suppressor gene Pten, a lipid phosphatase, is the primary negative regulator of PI3K in T cells. Using mice with Pten deficiency targeted to Tregs, as well as chemical inhibitors of PI3K, we are examining the role of PI3K in regulatory T cell homeostasis. Coupled to this project are studies of T cell metabolism as modulated by PI3K, and the degree to which glycolysis vs. oxidative metabolism can dictate T cell fate and function. The last major focus is the role of Toll-like receptors (TLRs) and the coupled adaptor protein MyD88 in T cells. TLRs are expressed on activated T cells and provide survival and costimulatory signals and may regulate cellular energy utilization pathways and thus fate determination. These observations are currently being explored in vivo models of immune responses such as infection and transplantation using T cell specific MyD88-deficient animals.
