Cell-Intrinsic Transforming Growth Factor-β Signaling Mediates Virus-Specific CD8+ T Cell Deletion and Viral Persistence In Vivo

被引:222
作者
Tinoco, Roberto [1 ]
Alcalde, Victor [1 ]
Yang, Yating [2 ]
Sauer, Karsten [2 ]
Zuniga, Elina I. [1 ]
机构
[1] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA
[2] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA
基金
美国国家卫生研究院;
关键词
HEPATITIS-C-VIRUS; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; PLASMACYTOID DENDRITIC CELLS; NATURAL-KILLER-CELL; TGF-BETA; INTERLEUKIN-10; RECEPTOR; IMMUNE-RESPONSES; PD-1; EXPRESSION; B-VIRUS;
D O I
10.1016/j.immuni.2009.06.015
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Although deficient CD8(+) T cell responses have long been associated with chronic viral infections, the underlying mechanisms are still unclear. Here we report that sustained transforming growth factor-beta (TGF-beta) expression and phosphorylation of its signaling mediator, Smad-2, Were distinctive features of virus-specific CD8(+) T cells during chronic versus acute viral infections in vivo. The result was TGF-beta-dependent apoptosis of virus-specific CD8(+) T cells that related to upregulation of the proapoptotic protein Bim during chronic infection. Moreover, selective attenuation of TGF-beta signaling in T cells increased the numbers and multiple functions of antiviral CD8(+) T cells and enabled rapid eradication of the persistence-prone virus and memory generation. Finally, we found that cell-intrinsic TGF-beta signaling was responsible for virus-specific-CD8(+) T cell apoptosis and decreased numbers but was not necessary for their functional exhaustion. Our findings reveal persisting TGF-beta-Smad signaling as a hallmark and key regulator of CD8(+) T cell responses during chronic viral infections in vivo.
引用
收藏
页码:145 / 157
页数:13
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