Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Laboratory of Immunoparasitology, World Premier International Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
J Exp Med. 2021 Jul 5;218(7). doi: 10.1084/jem.20201763. Epub 2021 May 10.
Because of their common signaling molecules, the main T cell receptor (TCR) signaling cascades in CD4+ and CD8+ T cells are considered qualitatively identical. Herein, we show that TCR signaling in CD8+ T cells is qualitatively different from that in CD4+ T cells, since CD8α ignites another cardinal signaling cascade involving phospholipase C β4 (PLCβ4). TCR-mediated responses were severely impaired in PLCβ4-deficient CD8+ T cells, whereas those in CD4+ T cells were intact. PLCβ4-deficient CD8+ T cells showed perturbed activation of peripheral TCR signaling pathways downstream of IP3 generation. Binding of PLCβ4 to the cytoplasmic tail of CD8α was important for CD8+ T cell activation. Furthermore, GNAQ interacted with PLCβ4, mediated double phosphorylation on threonine 886 and serine 890 positions of PLCβ4, and activated CD8+ T cells in a PLCβ4-dependent fashion. PLCβ4-deficient mice exhibited defective antiparasitic host defense and antitumor immune responses. Altogether, PLCβ4 differentiates TCR signaling in CD4+ and CD8+ T cells and selectively promotes CD8+ T cell-dependent adaptive immunity.
由于其共同的信号分子，CD4+和 CD8+ T 细胞中的主要 T 细胞受体 (TCR) 信号级联被认为在质量上是相同的。在此，我们表明，CD8+ T 细胞中的 TCR 信号在质量上不同于 CD4+ T 细胞，因为 CD8α 引发了另一个涉及磷脂酶 Cβ4 (PLCβ4) 的主要信号级联。在缺乏 PLCβ4 的 CD8+ T 细胞中，TCR 介导的反应严重受损，而在 CD4+ T 细胞中则完好无损。缺乏 PLCβ4 的 CD8+ T 细胞显示外周 TCR 信号通路在 IP3 生成后下游的激活受到干扰。PLCβ4 与 CD8α 胞质尾部的结合对于 CD8+ T 细胞的激活很重要。此外，GNAQ 与 PLCβ4 相互作用，介导 PLCβ4 上苏氨酸 886 和丝氨酸 890 位置的双磷酸化，并以 PLCβ4 依赖的方式激活 CD8+ T 细胞。缺乏 PLCβ4 的小鼠表现出寄生虫防御和抗肿瘤免疫反应缺陷。总之，PLCβ4 区分了 CD4+ 和 CD8+ T 细胞中的 TCR 信号，并选择性地促进了 CD8+ T 细胞依赖性适应性免疫。
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