Division of Cell Biology, La Jolla Institute for Immunology, La Jolla, CA 92037.
Division of Cell Biology, La Jolla Institute for Immunology, La Jolla, CA 92037
J Immunol. 2020 May 1;204(9):2439-2446. doi: 10.4049/jimmunol.1900963. Epub 2020 Mar 20.
We reported that protein kinase C-η (PKCη) forms a novel (to our knowledge) signaling complex with the checkpoint inhibitory protein CTLA-4 in regulatory T cells (Tregs). This complex is required for the contact-dependent suppressive activity of Tregs, including suppression of antitumor immunity. However, the importance of PKCη in protective immunity mediated by T effector cells remains unclear. We used mice with germline or conditional Treg-specific deletion of , the PKCη-encoding gene, to explore CD8 T cell-dependent antiviral immunity using the lymphocytic choriomeningitis virus Armstrong strain acute infection model as well as the in vitro activation of murine or human CD8 T cells. Five days following infection, germline mice displayed enhanced viral clearance compared with control mice. Similarly, Treg-specific conditional knockout mice also showed improved viral clearance and displayed enhanced expression of granzyme B and IFN-γ by both virus-specific and total CD8 T cells, demonstrating that enhanced viral clearance in germline mice is caused by PKCη deficiency in Tregs and the resulting functional defect of Tregs. In addition, purified mouse CD8 T cells as well as knockdown human CD8 T cells displayed intact, or even enhanced, T cell activation in vitro as measured by proliferation and expression of granzyme B and IFN-γ. Thus, global PKCη deletion does not impair overall CD8 T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCη inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor-specific and, likely, virus-specific immunity.
我们曾报道蛋白激酶 C-η（PKCη）与调节性 T 细胞（Tregs）中的细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）抑制蛋白形成一种新颖（据我们所知）的信号复合物。该复合物是 Tregs 接触依赖性抑制活性所必需的，包括抑制抗肿瘤免疫。然而，PKCη 在 T 效应细胞介导的保护性免疫中的重要性仍不清楚。我们使用基因敲除或条件性敲除编码 PKCη 的基因（）的 Treg 特异性小鼠，利用淋巴细胞性脉络丛脑膜炎病毒 Armstrong 株急性感染模型以及体外激活小鼠或人 CD8 T 细胞，来研究 CD8 T 细胞依赖性抗病毒免疫。感染后 5 天，基因敲除小鼠与对照小鼠相比，病毒清除能力增强。同样，条件性敲除 Treg 特异性的小鼠也显示出更好的病毒清除能力，并且病毒特异性和总 CD8 T 细胞均表现出颗粒酶 B 和 IFN-γ 的表达增强，表明基因敲除小鼠中增强的病毒清除是由 Tregs 中的 PKCη 缺失以及由此导致的 Tregs 功能缺陷引起的。此外，纯化的 小鼠 CD8 T 细胞以及敲低的人 CD8 T 细胞在体外表现出完整的，甚至增强的 T 细胞激活，如增殖和颗粒酶 B 和 IFN-γ 的表达。因此，全局 PKCη 缺失不会损害包括抗病毒免疫在内的总体 CD8 T 细胞介导的免疫，这意味着选择性的药理学 PKCη 抑制可以在体内安全地用于抑制 Tregs 的不希望的接触依赖性抑制，从而增强肿瘤特异性和可能的病毒特异性免疫。
