A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection.
A temporal role of type I interferon signaling in CD8+ T cell maturation during acute West Nile virus infection.
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DOI：
10.1371/journal.ppat.1002407
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Pinto AK;Daffis S;Brien JD;Gainey MD;Yokoyama WM;Sheehan KC;Murphy KM;Schreiber RD;Diamond MS
A genetic absence of the common IFN- α/β signaling receptor (IFNAR) in mice is associated with enhanced viral replication and altered adaptive immune responses. However, analysis of IFNAR-/- mice is limited for studying the functions of type I IFN at discrete stages of viral infection. To define the temporal functions of type I IFN signaling in the context of infection by West Nile virus (WNV), we treated mice with MAR1-5A3, a neutralizing, non cell-depleting anti-IFNAR antibody. Inhibition of type I IFN signaling at or before day 2 after infection was associated with markedly enhanced viral burden, whereas treatment at day 4 had substantially less effect on WNV dissemination. While antibody treatment prior to infection resulted in massive expansion of virus-specific CD8+ T cells, blockade of type I IFN signaling starting at day 4 induced dysfunctional CD8+ T cells with depressed cytokine responses and expression of phenotypic markers suggesting exhaustion. Thus, only the later maturation phase of anti-WNV CD8+ T cell development requires type I IFN signaling. WNV infection experiments in BATF3 -/- mice, which lack CD8-α dendritic cells and have impaired priming due to inefficient antigen cross-presentation, revealed a similar effect of blocking IFN signaling on CD8+ T cell maturation. Collectively, our results suggest that cell non-autonomous type I IFN signaling shapes maturation of antiviral CD8+ T cell response at a stage distinct from the initial priming event. Although it is well established that type I IFN responses protect against viral infections by inducing expression of antiviral genes and modulators of adaptive immune responses, its function at different stages of viral infections has remained poorly studied. In this paper, we administered a monoclonal antibody that blocks the common type I IFN signaling receptor to mice at different times after WNV infection to dissect the temporal functions of IFN. Administration of the blocking antibody at day -1 resulted in a massive increase in viral replication and the number of WNV-specific -CD8+ T cells. In contrast, treatment with a single dose of antibody at day 4 had limited effects on viral dissemination, but instead promoted development of dysfunctional CD8+ T cells that produced lower levels of cytokines and expressed proteins implicated in T cell exhaustion. Thus, we show a stage-specific effect of type I IFN in optimal maturation of antiviral CD8+ T cell responses. Our study provides new insight as to how and when innate immune signals affect maturation of antiviral CD8+ T cells after the initial priming event with viral antigen.
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影响因子：
3.7
作者：
Beasley, DWC;Li, L;Barrett, ADT
通讯作者：
Barrett, ADT
影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
DOI：
10.1073/pnas.0602460103
发表时间：
2006-05-16
影响因子：
11.1
作者：
Delhaye, Sophie;Paul, Sophie;Michiels, Thomas
通讯作者：
Michiels, Thomas
影响因子：
5.4
作者：
Frenz, Theresa;Waibler, Zoe;Kalinke, Ulrich
通讯作者：
Kalinke, Ulrich
影响因子：
5.4
作者：
Daffis, Stephane;Lazear, Helen M.;Diamond, Michael S.
通讯作者：
Diamond, Michael S.