Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2010: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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Research Abstract |
During chronic viral infection, persistent exposure to viral antigens leads to the overexpression of multiple inhibitory cell-surface receptors that cause CD8^+T cell exhaustion. Friend virus(FV) is a murine retrovirus complex that induces acute high-level viremia followed by persistent infection and leukemia development. Here we provide conclusive evidence that FV infection results in the generation of virus-specific effector CD8^+T cells that are terminally exhausted. Acute FV-induced disease is characterized by a rapid increase in the number of virus-infected erythroblasts, leading to massive splenomegaly. Most of the expanded erythroblasts strongly express PD-L1 and MHC class I, thereby creating a highly tolerogenic environment. Consequently, FV-specific effector CD8^+T cells uniformly express multiple inhibitory receptors, such as PD-1, Tim-3, LAG-3, and CTLA-4, rapidly become non-responsive to restimulation, and are no longer reinvigorated by combined in vivo blockade of PD-1 and Tim-3 during the memory phase. Combined blockade of PD-1 and Tim-3 during the priming/differentiation phase, however, rescued FV-specific CD8^+T cells from becoming terminally exhausted, resulting in improved CD8^+T cell functionality and virus control. These results highlight FV's unique ability to evade virus-specific CD8^+T cell responses and the importance of an early prophylactic approach for preventing terminal exhaustion of CD8^+T cells.
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