HTLV Deregulation of CD40(L) in Cancer&Neurodegeneration

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DESCRIPTION (provided by applicant): The cellular immune response mediated by cytotoxic T lymphocytes (CTLs) plays a critical role in the identification and clearance of human T cell lymphotropic virus type I (HTLV-I)-infected cells. Functional abnormalities in CTL-based cellular immunity are thought to play a significant role in the genesis of leukemia and neuroinflammatory disease that is associated with HTLV-I infection. Whereas an inefficient CTL response likely contributes to the development of adult T cell leukemia (ATL), a hyperactive CTL compartment may mediate inflammation within the central nervous system (CNS) in individuals with HTLV-l-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The long-term goal of the proposed investigations is to define the molecular mechanisms of HTLV-I-mediated deregulation of the cellular immune response, which leads to cancer and neurologic disease. This proposal is centered on the deregulated expression of CD40 Ligand (CD40L) and its receptor CD40 in HTLV-l-infected T cells. The CD40/CD40Lsystem is critical for orchestrating both cellular and humoral immune responses. CD40L is a costimulatory molecule that is transiently expressed on activated CD4+ T cells and binds to CD40 on dendritic cells (DCs) and induces functional maturation allowing for efficient activation of antiviral CD8+ T cells. The objective of this proposal is to determine the mechanism underlying the HTLV-I-mediated deregulation of CD40 andCD40L, and the functional effects on the cellular immune response as a result of the deregulation of these immune mediators. The focus will be to determine how HTLV-I modulates cellular signaling pathways and transcriptional control mediating CD40 and CD40L gene expression. The specific aims of this proposal are to determine (1) the mechanism of CD40 transcriptional activation in HTLV-I-infected T lymphocytes; (2) the effects of CD40 on activation, proliferation and CD40L expression in HTLV-l-infected T lymphocytes; (3) the effects of HTLV-I and HTLV-I Tax on the transcriptional regulation of CD40L; and (4) the impact of deregulated expression of CD40 and CD40L on the immune response to HTLV-I. Completion of the proposed studies may lead to therapeutic strategies of immune modulation, which could prevent leukemia and/or neuroinflammatory disease.