Our goal in this project is to develop efficient methods for making a class of immune-system cells known as regulatory T cells (Tregs), that have the potential to be useful in a wide variety of clinical situations. Tregs control the harmful immune responses seen in patients with autoimmune diseases including childhood (Type I) diabetes, rheumatoid arthritis, multiple sclerosis and inflammatory bowel disease; they also suppress rejection of transplanted organs in patients given heart, liver or kidney transplants. We proposed to ask whether three proteins known as TET proteins, recently discovered in our laboratory, had a role in Treg development and function. We also proposed to develop efficient ways to make Tregs from different types of stem cells.
With regard to the second objective, we have now made the interesting discovery that mice lacking two of the three Tet proteins develop an enlarged spleen and other features which suggest that they possess diminished numbers of functional Tregs. This will allow us to understand Treg development and function at a molecular level. With regard to the first objective, we are examining the entire set of transcripts present in different forms of Tregs and their precursors through next-generation sequencing of RNA. We anticipate that introduction of combinations of these factors into precursor cells of various types will lead to the successful generation of Tregs in cell culture.
Although our research will be done mostly in animals (mice), we believe that it will be possible to translate it quickly into humans, and that if successful, it will address a pressing clinical need. For patients receiving transplanted organs, we hope to take their own normal T cells and turn them into Tregs. For patients suffering from autoimmune diseases, it would be useful to make Tregs artificially from their bone marrow stem cells, whereas for cancer patients who have been given chemotherapy followed by a bone marrow transplant from a different person, it would be useful to make Tregs from the same bone marrow cells that the patient receives, in the hope that these Tregs can suppress graft-versus-host disease. We believe that all these approaches are feasible in principle, given recent discoveries from our own and other labs.