Yamada Takeshi, Kanoh Makoto, Nabe Shogo, Yasuoka Toshiaki, Suzuki Junpei, Matsumoto Akira, Kuwahara Makoto, Maruyama Saho, Fujimoto Takuya, Sakisuka Ryo, Yasukawa Masaki, Yamashita Masakatsu
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan;
Department of Infection and Host Defenses, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
J Immunol. 2016 Nov 15;197(10):4079-4089. doi: 10.4049/jimmunol.1502295. Epub 2016 Oct 19.
Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8 T cells remains unclear. We generated Menin CD4-Cre (Menin-KO) mice by crossing Menin mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8 T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8 T cells. Menin deficiency resulted in an impaired primary immune response by CD8 T cells. On day 7, there were fewer Menin-KO OVA-specific CD8 T cells compared with WT cells. Next, we adoptively transferred WT and Menin-KO OT-1 Tg CD8 T cells into congenic recipient mice and infected them with L. monocytogenes expressing OVA to determine the CD8 T cell-intrinsic effect. Menin-KO OT-1 Tg CD8 T cells were outcompeted by the WT cells upon infection. Increased expression of Blimp-1 and T-bet, cell cycle inhibitors, and proapoptotic genes was observed in the Menin-KO OT-1 Tg CD8 T cells upon infection. These data suggest that menin inhibits differentiation into terminal effectors and positively controls proliferation and survival of Ag-specific CD8 T cells that are activated upon infection. Collectively, our study uncovered an important role for menin in the immune response of CD8 T cells to infection.
Menin是一种肿瘤抑制蛋白，由人类的MEN1基因编码。MEN1的某些胚系突变会诱发一种常染色体显性综合征，其特征为并发甲状旁腺腺瘤和其他几种肿瘤类型。尽管Menin也在造血谱系中表达，但其在CD8 T细胞中的作用仍不清楚。我们通过将Menin小鼠与CD4-Cre转基因（Tg）小鼠杂交，生成了Menin CD4-Cre（Menin-KO）小鼠，以确定Menin在CD8 T细胞中的作用。用表达OVA的单核细胞增生李斯特菌感染野生型（WT）和Menin-KO小鼠，以分析抗原特异性CD8 T细胞的免疫反应。Menin缺陷导致CD8 T细胞的初次免疫反应受损。在第7天，与WT细胞相比，Menin-KO OVA特异性CD8 T细胞数量更少。接下来，我们将WT和Menin-KO OT-1 Tg CD8 T细胞过继转移到同基因受体小鼠中，并用表达OVA的单核细胞增生李斯特菌感染它们，以确定CD8 T细胞内在效应。感染后，Menin-KO OT-1 Tg CD8 T细胞被WT细胞竞争淘汰。感染后，在Menin-KO OT-1 Tg CD8 T细胞中观察到Blimp-1和T-bet、细胞周期抑制剂和促凋亡基因的表达增加。这些数据表明，Menin抑制向终末效应细胞的分化，并正向调控感染后被激活的抗原特异性CD8 T细胞的增殖和存活。总的来说，我们的研究揭示了Menin在CD8 T细胞对感染的免疫反应中的重要作用。
