2011 Fiscal Year Final Research Report
Retrovirus evasion of CD8^+T cell immunity
| Project/Area Number |
22790441
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Virology
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| Research Institution | Kinki University |
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Principal Investigator |
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| Project Period (FY) |
2010 – 2011
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| Keywords | 感染防御 / ワクチン |
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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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[Journal Article] Chemokine receptor CXCR3 facilitates CD8^+T cell differentiation into short-lived effector cells leading to memory degeneration2011
Author(s)
Kurachi M, Kurachi J, Suenaga F, Tsukui T, Abe J, Ueha S, Tomura M, Sugihara K, Takamura S, Kakimi K, Matsushima K
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Journal Title
J Exp Med
Volume: 208(8)
Pages: 1605-20
URL
Peer Reviewed
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