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Affiliations
Director, Immuno/BioSpot Core
Professor, Pediatrics, Microbiology, Immunology & Molecular Genetics
Member, Cell & Developmental Biology GPB Home Area,Immunity, Microbes & Molecular Pathogenesis GPB Home Area, Tumor Immunology Program at the Jonsson Comprehensive Cancer Center (JCCC)

Research Interests
Human T cell development is the major focus of the laboratory. The thymus is the central organ where T cell receptor (TCR) alpha/beta cells as well as other rare hematopoietic cell types develop from intrathymic stem cells. These cell types include TCR gamma/delta cells, plasmacytoid (lymphoid -derived) dendritic cells, myeloid derived dendritic cells, Natural Killer (NK) cells, NK-T cells and regulatory T cells. These rare cell populations comprise potent immunoregulatory cells that link the innate and adaptive immune response as they carry out their function in the periphery against various pathogens such as human immunodeficiency virus (HIV). HIV actively replicates in the human thymus and disrupts normal T cell development contributing to the overall immune dysfunction seen in HIV infected individuals. This is particularly obvious during fetal and postnatal life when the thymus is most active. The focus of our laboratory is to: 1) elucidate factors such as chemokines and cytokines involved in thymopoiesis that can be exploited to boost T cell developmental processes; 2) investigate the function of intrathymic dendritic cells such as plasmacytoid dendritic cells, the natural Interferon-alpha (IFN-alpha) producing cells, and myeloid dendritic cells in normal T cell development; 3) evaluate the mechanism of the immunosuppressive effects of high levels of IFN-alpha observed in certain diseases ;4) examine the cytopathicity, replicative capacity, and cell tropism of various pediatric HIV isolates in the thymus; 5) determine the role of regulatory T cells in thymic HIV infection. We utilize three different model systems to study T cell development: in vitro thymocyte suspension culture, thymus organ culture, and human thymus grafts in the SCID-hu mouse. The goal of our research is to gain a better understanding of the development and function of the immune system in order to facilitate the development and design of novel therapeutic approaches to immunodeficiency such as observed after chemotherapy, bone marrow transplantation and in HIV disease.

Biography
Human T Cell Development Studies of human T cell development are the major focus of the laboratory. These studies are being pursued in in vitro thymocyte suspension cultures, thymic organ culture and in vivo in the SCID/hu mouse. We are interested in examining the role of cytokines on normal thymocyte maturation. We want to assess whether cytokine administration can augment stem cell reconstitution strategies in diseases such as infection with the human immunodeficiency virus (HIV) and malignancies. In addition, understanding the interaction between HIV and the developing T cell in the thymus is an important focus of the laboratory. Our studies are intended to test the hypotheses that: 1). thymocyte subsets which are activated and/or proliferating are the principle targets for HIV infection; 2). cytopathic viral strains affect thymocytes at an earlier stage of maturation than non-cytopathic strains and 3). depletion of thymocytes which produce IFN-g results in increased HIV expression by thymocytes and contributes to immunodeficiency. Studies of human T cell development are the major focus of the laboratory. These studies are being pursued are in vitro thymocyte suspension cultures, thymic organ cultures and in vivo in the SCID/hu mouse. We are interested in examining the role of cytokines on normal thymocyte maturation. We want to assess whether cytokine administration can augment stem cell reconstitution strategies in disease such as infection with the human immunodeficiency virus (HIV) and malignancies. In addition, understanding the interaction between HIV and the developing T cell in the thymus is an important focus of the laboratory. Our studies are intended to test the hypothesis that: 1) thymocyte subsets which are activated and/or proliferating are the targets for HIV infection; 2) cytopathic viral strains affect thymocytes at an earlier stage of maturation than non-cytopathic strains and 3) depletion of thymocytes which produce IFN-. results in increased HIV expression by thymocytes and contribution to immunodeficiency. Besides studying the effects of HIV on the developing immune system, we are continuing our research to determine how cytokines affect cell growth and the phenotype of malignant immature T cell leukemias. We have shown that there is a correlation between stage of maturation of the T cell leukemias and expression of the transcription factor c-jun which binds to the AP-1 binding site. Therefore, we want to delineate the role of the nuclear factors in normal and malignant T cell growth and differentiation. Understanding the normal developing immune system and its deregulation in HIV disease and leukemias may provide new avenues for medical intervention.

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