Dok-1 和 Dok-2 调节记忆 CD8+T 细胞的形成,The Journal of Immunology

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Dok-1 和 Dok-2 调节记忆 CD8+T 细胞的形成
The Journal of Immunology ( IF 3.6 ) Pub Date : 2016-09-23 , DOI: 10.4049/jimmunol.1600385
Constance Laroche-Lefebvre ₁ , Mitra Yousefi ₁ , Jean-François Daudelin ₂ , Tania Charpentier ₁ , Esther Tarrab ₁ , Roscoe Klinck ₃ , Alain Lamarre ₁ , Nathalie Labrecque ₂ , Simona Stäger ₁ , Pascale Duplay ₁

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CD8+ T 细胞接收到的不同信号被整合，以实现所需的细胞扩增幅度和效应器/记忆 CD8+ T 细胞生成的适当平衡。值得注意的是，TCR 信号的强度和性质影响效应和记忆 CD8+ T 细胞的分化和功能能力。Dok-1 和 Dok-2 是在 T 细胞中表达的 Dok 家族的两个成员，它们在体外负向调节 TCR 信号。然而，Dok 蛋白在体内调节 T 细胞功能的作用尚未研究。我们研究了 Dok-1 和 Dok-2 蛋白在调节 CD8+ T 细胞对痘苗病毒感染的反应中的功能。野生型和 Dok-1/2−/− CD8+ OT-I 细胞对表达 OVA 肽 SIINFEKL 的痘苗病毒的反应的比较表明，Dok-1 和 Dok-2 的缺失略微降低了病毒特异性效应子 CD8+ 的量级T细胞扩增。这不是由于效应 CD8+ T 细胞的增殖减少或凋亡增强。Dok-1/2 缺陷型效应 CD8+ T 细胞在体内病毒感染后显示出细胞表面 TCR 表达增加，并在体外用肽 Ag 刺激后增加颗粒酶 B 和 TNF 的表达。最后，Dok-1/2 缺陷型效应子 CD8+ T 存在严重的存活缺陷，导致记忆 CD8+ T 细胞的生成受损。这些结果揭示了 Dok-1 和 Dok-2 在负反馈循环中的关键参与，可防止 CD8+ T 细胞过度激活并促进记忆形成。

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Dok-1 and Dok-2 Regulate the Formation of Memory CD8+T Cells

Diverse signals received by CD8+ T cells are integrated to achieve the required magnitude of cell expansion and the appropriate balance of effector/memory CD8+ T cell generation. Notably, the strength and nature of TCR signaling influence the differentiation and functional capacity of effector and memory CD8+ T cells. Dok-1 and Dok-2, the two members of the Dok family expressed in T cells, negatively regulate TCR signaling in vitro. However, the role of Dok proteins in modulating T cell function in vivo has not yet studied. We studied the function of Dok-1 and Dok-2 proteins in the regulation of the CD8+ T cell response to vaccinia virus infection. Comparison of responses to vaccinia virus expressing OVA peptide SIINFEKL by wild-type and Dok-1/2−/− CD8+ OT-I cells showed that the absence of Dok-1 and Dok-2 slightly reduced the magnitude of virus-specific effector CD8+ T cell expansion. This was not due to reduced proliferation or enhanced apoptosis of effector CD8+ T cells. Dok-1/2–deficient effector CD8+ T cells showed increased cell surface TCR expression following virus infection in vivo and increased expression of granzyme B and TNF upon stimulation with peptide Ag ex vivo. Finally, Dok-1/2–deficient effector CD8+ T had a severe defect in survival that resulted in impaired generation of memory CD8+ T cells. These results reveal the critical involvement of Dok-1 and Dok-2 in a negative-feedback loop that prevents overactivation of CD8+ T cells and promotes memory formation.

更新日期：2016-09-23

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