CD8 +调节性T细胞活性的遗传破坏增强对病毒感染的免疫反应

StephenW

Genetic disruption of CD8+ Treg activity enhances the immune response to viral infection

    Tobias A. W. Holderrieda,b,c,
    Philipp A. Langc,
    Hye-Jung Kima,b,1,2, and
    Harvey Cantora,b,1,2

Author Affiliations

    Contributed by Harvey Cantor, November 14, 2013 (sent for review October 25, 2013)

Significance

Cellular interactions that regulate the immune response of T cells to viral infection are poorly understood. Here we report that in the absence of activity of CD8 regulatory T-cells (CD8 Treg cells), antiviral immunity is enhanced and the deleterious effects of viral infection are constrained. Using a genetically modified mouse model that displays defective regulatory activity of CD8 Treg cells, the immune response against viruses was substantially enhanced during the acute and chronic phase of viral infection; this enhanced antiviral response prevented tissue damage associated with viral infection. This suggests that protective immunity to viral infection can be achieved by blocking the inhibitory effects of CD8 Treg cells and opens the possibility of unique approaches to treat viral infection.

Abstract

The immunological interactions that regulate the T-cell response to chronic viral infection are insufficiently understood. Here we study a cellular interaction that may enhance the antiviral immune response and constrain immunopathology. We analyze the contribution of Qa-1-restricted CD8+ regulatory T cells (Treg cells) to antiviral immunity after infection by lymphocytic choriomeningitis virus. These CD8+ Treg cells recognize and eliminate target cells through an interaction with the murine class Ib MHC molecule Qa-1 (HLA-E in humans). Using Qa-1 mutant mice (B6.Qa-1-D227K [B6-DK]) that harbor a single mutation that abrogates binding of Qa-1 peptide to the CD8–TCR (T-cell receptor) complex, we show that disruption of immune suppression mediated by CD8+ Treg cells results in robust antiviral immune responses in both acute and chronic viral infection. Enhanced antiviral responses of B6-DK mice were accompanied by increased control of virus, reduced tissue inflammation in the acute phase, and dramatic alleviation of disease in the chronic phase. In addition, CD8+ effector T cells in B6-DK mice displayed a less exhausted phenotype characterized by decreased expression of programmed cell death 1 (PD-1), LAG3 (CD223), and 2B4 (CD244) and increased expression of NKG2D (CD314) and killer cell lectin-like receptor subfamily G member 1 (KLRG1). Enhanced antiviral immunity in B6-DK mice reflected, in part, reduced inhibition of CD8+ effector cells by CD8+ Treg cells. These findings indicate that direct inhibition of effector CD8+ T cells by Qa-1-restricted CD8+ Treg cells results in increased disease severity and delayed recovery. These data suggest that depletion or inactivation of CD8+ Treg cells represents a potentially effective strategy to enhance protective immunity to chronic viral infection.

    T-cell exhaustion
    killer cell Ig-like receptor
    immune regulation

Footnotes

    1H.-J.K. and H.C. contributed equally to this work.
    2To whom correspondence may be addressed. E-mail: [email protected] or [email protected].

    Author contributions: T.A.W.H., P.A.L., H.-J.K., and H.C. designed research; T.A.W.H. and H.-J.K. performed research; T.A.W.H., P.A.L., H.-J.K., and H.C. analyzed data; and T.A.W.H., P.A.L., H.-J.K., and H.C. wrote the paper.

    The authors declare no conflict of interest.

StephenW

CD8 +调节性T细胞活性的遗传破坏增强对病毒感染的免疫反应

    托比亚斯A. W. Holderrieda ， B，C ，
    菲利普A. Langc ，
    惠荣基马， B， 1,2 ，和
    哈维Cantora ， B， 1,2

作者所属机构

    供稿人：哈维·康托尔， 2013年11月14日（送审查2013年10月25日）

意义

调节性T细胞对病毒感染的免疫应答的细胞相互作用了解甚少。此处我们报告，在没有CD8调节性T细胞（ CD8 + Treg细胞）的活性，抗病毒免疫增强和病毒感染的有害影响被限制。使用该显示的CD8 T细胞的缺陷的调节活性的遗传修饰的小鼠模型中，对病毒的免疫应答过程中的病毒感染的急性期和慢性期，大幅提升，这增强抗病毒反应抑制与病毒感染有关的组织损伤。这表明，保护性免疫的病毒感染可通过阻断CD8 T细胞的抑制作用来实现打开和独特的方法来治疗病毒感染的可能性。

摘要

调节的T细胞应答的慢性病毒感染的免疫学相互作用是不充分的理解。在这里，我们研究了细胞的互动，可以提高抗病毒免疫反应和免疫病理学约束。我们分析的Qa- 1限制性CD8 +调节性T细胞（ Treg细胞）的感染后，抗病毒免疫由淋巴细胞性脉络丛脑膜炎病毒的贡献。这些CD8 + Treg细胞通过交互识别和消除靶细胞与鼠Ib类MHC分子QA - 1 （ HLA-E在人体内） 。使用的Qa- 1突变体小鼠（ B6.Qa -1- D227K [ B6- DK] ）窝藏单一突变废除的QA -1肽结合到CD8- T细胞受体（ T细胞受体）复合物，我们表明，受阻的免疫抑制由CD8 + Treg细胞的结果在急性和慢性病毒感染鲁棒抗病毒的免疫反应所介导。伴随着病毒的增加的控制，减少组织炎症在急性期和疾病显着减轻慢性期B6 -DK小鼠增强抗病毒反应。另外， CD8 +效应T细胞在B6 -DK小鼠显示一个用尽量少的表型特征的表达减少细胞程序性死亡-1（ PD -1）， LAG3 （ CD223 ） ，并且2B4 （ CD244 ）和NKG2D表达的增加（ CD314 ）和杀伤细胞凝集素样受体亚家族摹成员1 （ KLRG1 ） 。在B6 -DK小鼠增强抗病毒免疫反映，部分降低CD8 +调节性T细胞抑制CD8 +效应细胞。这些结果表明，通过直接抑制效应CD8 + T细胞的的Qa- 1限制性CD8 + Treg细胞导致增加的疾病的严重程度和延迟恢复。这些数据表明，耗尽的CD8 + T细胞或失活代表一种潜在的有效的策略，以提高保护性免疫慢性病毒感染。

    T细胞耗竭
    杀伤细胞免疫球蛋白样受体
    免疫调节

脚注

    1H.-J.K.和H.C.同等贡献这项工作。
    2要谁信件可能得到解决。电子邮件： [email protected]或[email protected] 。

    作者贡献： TAWH ， PAL制式， H.- JK ，和HC设计研究; T.A.W.H.和H.-J.K.进行研究; TAWH ， PAL制式， H.- JK ，和HC分析数据，以及TAWH ， PAL ， H.- JK ，和HC写文章。

    作者宣称没有利益冲突。