Efficient T cell development from human pluripotent stem cells by LRF/Pokemon inactivation
T cells (or T lymphocytes) are necessary for normal immune surveillance systems, and their dysfunction leads to development of fatal diseases, such as Acquired Immune Deficiency Syndrome (AIDS), congenital T cell deficiency and cancer. These diseases are life threatening, because T cells, key effectors eradicating pathogens within the body, are severely reduced and medications (e.g. anti-viral treatment) cannot fully compensate for such fundamental defects. Thus, in these circumstances, providing T cells to the patient, so-called “T cell replacement therapy”, could be the sole therapeutic option to cure the disease. However, such therapy has not been successfully established because of the following reasons: 1) T cells are difficult to expand in culture; 2) even if the patient’s T cells can be expanded in culture, they may not work normally when they are returned to the patient (e.g. T cells will be again infected with HIV virus) and 3) T cells from others (donor) could recognize the patient (recipient) as "foreign" and mount an immunologic attack.
Human pluripotent stem cells, such as human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs), have tremendous potential in T cell replacement therapy, as: 1) they are virtually unlimited; 2) patient-specific hiPSCs can overcome immunological barriers between donors and recipients and 3) hESCs/hiPSCs could be safely manipulated for T cells to be functional. While T cells have been successfully derived from mouse embryonic stem cells (mESCs), hESCs demonstrated little lymphoid potential, preventing the use of hESCs for T cell replacement therapy. Considering clinical implications, there is a critical need to better understand the mechanisms underlying hESCs/hiPSCs differentiation toward T cells.
Our goal is to develop a system by which hESCs/hiPSCs efficiently give rise to T cells in culture. The objective of this application is to determine the role of the Leukemia/lymphoma Related Factor (LRF) gene in human T cell differentiation from hESCs/hiPSCs. Guided by our preliminary studies, we hypothesize that LRF inactivation promotes efficient T cell development from hESCs/hiPSCs. We will test this hypothesis employing molecular biological approaches as well as a series of genetically engineered mouse models. We expect that the combination of work proposed will provide further understanding of how hESCs/hiPSCs develop T cells in culture. This contribution is significant because it will lead to the development of new therapeutic strategies for T cell replacement therapy.
T cells are essential for human immune system and the lack of functional T cells results in development of diseases such as AIDS, sever infectious diseases and cancer. These diseases are one of the major health issues in California. It has been estimated that nearly 130,000 people in California live with human immunodeficiency virus (HIV) infection, among which 70,000 are diagnosed as AIDS (HIV Prevalence Estimates of California, CDC, 2008). For these patients, providing healthy and functional T cells, so-called T cell replacement therapy, could be a new therapeutic strategy, as current therapies (e.g. anti-viral drag for AIDS, chemotherapy for cancer) cannot cure the disease, and cost of the treatment is high. Human pluripotent stem cells (hPSCs) are a very promising source for such T cells, as they are virtually unlimited and relatively easy to be manipulated in culture (e.g. gene therapy for AIDS and cancer). However, it is not fully understood how hPSCs differentiate to T cells, preventing their use in the clinic. Our goal is to develop a new way of creating T cells from hPSCs in culture by elucidating the molecular mechanisms of T cell development from hPSCs. If successful, it will provide the people of California with tremendous benefits, potentially leading to new therapeutic strategies for life-threatening diseases such as cancer and AIDS. It may also lead to the significant reduction of therapeutic costs, thus benefiting the State economy.