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Thesis Advisor: Dr. Arnold Rabson
Gradutae Program: Molecular Genetics, Microbiology and Immunology
Friday, August 21, 2009
Infection with the human T cell leukemia virus-1 (HTLV-1) results in a variety of diseases including adult T cell leukemia/lymphoma (ATL). The pathogenesis of these disorders is poorly understood, however involves complex interactions with the host immune system. Activation of infected T cells may play an important role in disease pathogenesis through induction of the oncogenic HTLV-1 Tax transactivator protein. To study this hypothesis, we employed transgenic mice in which Tax is regulated by the HTLV-1 LTR. T cell receptor-stimulation of LTR-Tax CD4+ T cells induced Tax expression, hyper-proliferation, and immortalization in culture. The transition to cellular immortalization was accompanied by markedly increased expression of the anti-apoptotic gene, mcl-1, previously implicated as important in T cell survival, and the marked increased of the pro-apoptotic gene, Bim, a critical regulator of T cell population contraction and death. Immortalized cells exhibited a CD4+CD25+CD3- phenotype commonly observed in ATL. Engraftment of activated LTR-Tax CD4+ T-cells into NOD/Shi-scid/IL-2Rgamma null mice resulted in a leukemia-like phenotype with expansion and tissue infiltration of Tax+, CD4+ lymphocytes. We suggest that immune activation of infected CD4+ T cells plays an important role in the induction of Tax expression, T cell proliferation, and pathogenesis of ATL in HTLV-1-infected individuals.