In Vitro Differentiation of T cells from Human Embryonic Stem Cells.

White blood cells are the main players of human immunity in defense against infection. Defects in CD4 T white blood cells, for example, can lead to the devastating infections observed in AIDS patients and patients with a genetic immunodeficiency syndrome (“bubble boy” syndrome). A normal immune system can recognize and attack pathogens but not “self”. This is achieved by rigorous selection and “education” during development of T or B white blood cells and by regulatory T cells that suppress occasional “run-away” white blood cells. Glitches in these processes can also lead to equally devastating problems as seen in many autoimmune diseases like type I diabetes, multiple sclerosis and rheumatoid arthritis. Thus, the availability of T cells or regulatory cells could lead to therapies for many human diseases.

A major limitation in using T cells in therapy is the lack of available primary T cells generated in the laboratory. Attempts thus far to generate T cell precursors in a tissue culture dish from the existing NIH approved embryonic stem (ES) cell lines have had only limited success, perhaps due to the partial white blood cell potential of these particular lines. Efficient conversion of T cell precursors into mature T cells or regulatory T cells in a tissue culture dish have also not yet been achieved.

In this seed grant application, we propose to test a series of new (non-federally approved) human embryonic stem (ES) cells for their abilities to efficiently generate white blood cells precursors and subsequently immature T cells in a tissue culture dish. Conditions to optimize generation of white blood cell precursors and T cell precursors will be sought. We will then examine how to convert mature T cells from T cell precursors by varying the culture conditions to closely mimick the “real” situation in humans. Successful completion of this project would constitute a major first step in the long-term goal of using human T cells (that can attack pathogens, but do not react to one’s own organs) in therapy. Examples of possible clinical therapy include administration of regulatory T cells in preventing autoimmune attacks in a variety of aforementioned autoimmune diseases. Availability of T cells specific for proteins found in tumors could be used to treat cancer, and mature T cell populations could be used to restore immune function of AIDS patients and to improve the short-term survival of bone marrow transplant recipients.