Immunodeficiencies (inherited or acquired) and lymphocyte malignancy are two major immune disorders that pose grave threats to public health. Firstly, loss of T cells in adults (e.g. due to chemotherapy or ageing) severely compromises cellular immunity. How the distinct CD4+ and CD8+ T cell identities are established and maintained remains an unanswered puzzling question at present. Secondly, acute T cell lymphoblastic leukemia/lymphomas (T-ALLs) is induced by the transformation of developing T cells in the thymus. Elucidation of factors/pathways contributing to initiation and propagation of T-ALLs is required to improve diagnosis and develop novel targeted therapies. Tcf1 and Lef1 transcription factors are well documented to have essential roles in T cell development. We also showed that Tcf1 functions as a tumor suppressor by restraining Lef1 and Notch expression in early thymocytes. Tcf1 and Lef1 are most notably associated with the Wnt--catenin pathway; however, the long- standing controversies regarding the physiological roles of -catenin in T cell development and malignancy remain unresolved. By conditionally targeting both Tcf1 and Lef1 at CD4+CD8+ double positive (DP) thymocytes, we found that Tcf1/Lef1 double deficient CD8+ T cells showed inappropriate expression of CD4+ lineage genes including the CD4 coreceptor itself, CD40 ligand, Rorgt and Foxp3 without prior activation. We hypothesize that Tcf1 and Lef1 seal off CD8+ T cell identity by epigenetically silencing CD4+-associated genes. We have generated a true -catenin null mutant and another mouse strain where Tcf1 long isoforms are ablated and hence Tcf1-- catenin interaction is abrogated. With these new tools, we will test the hypothesis that Tcf1 and Lef1 use both -catenin-dependent and -independent mechanisms to regulate thymocyte maturation and transformation.
Our specific aims are:
Specific Aim 1. To investigate the mechanisms by which Tcf1 and Lef1 regulate CD8+ T cell identity.
Specific Aim 2. To elucidate the requirements of -catenin and its interaction with Tcf1/Lef1 in T cell development and malignancy. These studies will identify the first transcription factors and their interaction with epigenetic machinery that re responsible for regulation of CD8+ T cell identity. The new animal models will ensure unprecedented clarity to resolve the long-standing controversies over -catenin. The outcomes will establish new paradigms in immune cell identity and the involvement of Wnt--catenin pathway. The information will identify critical regulatory points in directing hematopoietic progenitors or iPS cells to mature T cells with desired antigen specificity and thus help improve immune reconstitution and targeted, cell-based cancer therapy.
CD4 and CD8 T cells are critical components in cellular immunity that controls infection by bacteria, viruses, and other pathogens. This project will investigate the regulatory roles of Tcf1 and Lef1 transcription factors and their coactivator -catenin in regulating CD8 T cell identity and malignant transformation of thymocytes. The new knowledge will have profound impact on identifying critical regulatory points in directing progenitors to mature T cells with desired antigen specificity, which will be powerful tools to improve cell-based cancer therapy, immune reconstitution and infection control.
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