Statement of Benefit to California:
Year 1Many immune deficiencies are due to the loss of function of the thymus gland, the source of T lymphocytes, which are white blood cells needed for the immune system to protect our bodies from infections.. Thymic epithelial cells (TEC) are the skin-like cells in the thymus that allow the body to make T lymphocytes, TEC are damaged by cancer chemotherapy and radiation, HIV infection and in aging, resulting in loss of immune function. With the funding from CIRM, we developed techniques to make new TEC in vitro from embryonic stem cells (ESC). The methods that we use mimic the normal steps in the development of TEC during fetal life. These steps include receiving signals from neighboring cells, expression of a gene Tbx1 that controls whether cells can become TEC, and then receiving further signals from other nearby cells. Mixing the resulting test-tube generated TEC with immature blood stem cells allows the blood cells to develop into T lymphocytes in the same way that T lymphocytes are normally made in the thymus. The newly generated TEC can also be transplanted into mice and allow the animal to make new T lymphocytes. One way to test the ability of TEC made from human ESC to make human T cells is to transplant the cells into mice, which allow human cells to survive and develop. A mouse which will permit the development of human TEC is under development. In summary, the studies have established the methods to make new functional TEC from ESC, an important step in the ability to regenerate the thymus and treat immune disorders.