Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo
Dendritic Cells and CD28 Costimulation Are Required To Sustain Virus-Specific CD8+ T Cell Responses during the Effector Phase In Vivo
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DOI：
10.4049/jimmunol.1001972
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发表时间：
2011-04-15
影响因子：
4.4
通讯作者：
Katsikis, Peter D.
中科院分区：
文献类型：
--
作者：
Dolfi, Douglas V.;Duttagupta, Priyanka A.;Katsikis, Peter D.
尽管对免疫应答的启动已有很多了解，但对效应阶段的调控因素却知之甚少。据信，CD8(+) T细胞应答在启动期间于淋巴结中被编程设定，树突状细胞（DCs）和抗原（Ag）不再进一步发挥作用。在本研究中，我们报道了在CD8(+) T细胞应答的效应阶段需要DCs、Ag以及CD28共刺激。在甲型流感病毒初次感染第6天后清除DCs或阻断CD28，会通过诱导细胞凋亡减少病毒特异性CD8(+) T细胞应答，进而导致病毒清除能力下降。此外，在效应阶段过继转移的效应CD8(+) T细胞在没有DC、CD28共刺激以及同源Ag的情况下无法扩增。缺乏共刺激还会导致病毒特异性效应细胞因促凋亡分子Bim介导的细胞凋亡而存活率降低。最后，白细胞介素 - 2（IL - 2）处理可在缺乏CD28共刺激的情况下恢复效应应答。因此，与初始的不依赖Ag增殖的初始CD8(+) T细胞不同，在效应阶段于肺部扩增的效应CD8(+) T细胞需要Ag、CD28共刺激以及DCs来维持存活和扩增。这些需求会极大地削弱针对已知会抑制DC成熟的病毒和肿瘤的效应应答，以及在慢性感染和衰老过程中（此时CD28(-/-) CD8(+) T细胞会累积）的效应应答。《免疫学杂志》，2011年，186卷：4599 - 4608页。
Although much is known about the initiation of immune responses, much less is known about what controls the effector phase. CD8(+) T cell responses are believed to be programmed in lymph nodes during priming without any further contribution by dendritic cells (DCs) and Ag. In this study, we report the requirement for DCs, Ag, and CD28 costimulation during the effector phase of the CD8(+) T cell response. Depleting DCs or blocking CD28 after day 6 of primary influenza A virus infection decreases the virus-specific CD8(+) T cell response by inducing apoptosis, and this results in decreased viral clearance. Furthermore, effector CD8(+) T cells adoptively transferred during the effector phase fail to expand without DC, CD28 costimulation, and cognate Ag. The absence of costimulation also leads to reduced survival of virus-specific effector cells as they undergo apoptosis mediated by the proapoptotic molecule Bim. Finally, IL-2 treatment restored the effector response in the absence of CD28 costimulation. Thus, in contrast to naive CD8(+) T cells, which undergo an initial Ag-independent proliferation, effector CD8(+) T cells expanding in the lungs during the effector phase require Ag, CD28 costimulation, and DCs for survival and expansion. These requirements would greatly impair effector responses against viruses and tumors that are known to inhibit DC maturation and in chronic infections and aging where CD28(-/-) CD8(+) T cells accumulate. The Journal of Immunology, 2011, 186: 4599-4608.