Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA.
J Exp Med. 2022 Aug 1;219(8). doi: 10.1084/jem.20212434. Epub 2022 Jun 27.
IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12-dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading to NK cell proliferation and expansion is not established. Here, we show that IL-12 alone can sustain human primary NK cell survival without providing IL-2 or IL-15 but was insufficient to promote human NK cell proliferation. IL-12 signaling analysis revealed STAT5 phosphorylation and weak mTOR activation, which was enhanced by activating NK receptor upregulation and crosslinking leading to STAT5-dependent, rapamycin-sensitive, or TGFβ-sensitive NK cell IL-12-dependent expansion, independently of IL-12 receptor upregulation. Prolonged IL-2 culture did not impair IL-12-dependent ligand-specific NK cell expansion. These findings demonstrate that activating NK receptor stimulation promotes differential IL-12 signaling, leading to human NK cell expansion, and suggest adopting strategies to provide IL-12 signaling in vivo for ligand-specific IL-2-primed NK cell-based therapies.
IL-12 是一种重要的细胞因子，参与记忆或记忆样 NK 细胞的生成。小鼠巨细胞病毒感染触发 NK 受体诱导、配体特异性 IL-12 依赖性 NK 细胞扩增，但尚未确定特定的 IL-12 刺激体外导致 NK 细胞增殖和扩增。在这里，我们表明，IL-12 单独可以维持人原代 NK 细胞的存活，而无需提供 IL-2 或 IL-15，但不足以促进人 NK 细胞增殖。IL-12 信号分析显示 STAT5 磷酸化和弱 mTOR 激活，通过激活 NK 受体上调和交联增强，导致 STAT5 依赖性、雷帕霉素敏感性或 TGFβ 敏感性 NK 细胞 IL-12 依赖性扩增，而不依赖于 IL-12 受体上调。延长 IL-2 培养不会损害 IL-12 依赖性配体特异性 NK 细胞扩增。这些发现表明，激活 NK 受体刺激可促进不同的 IL-12 信号转导，从而导致人 NK 细胞扩增，并表明采用策略在体内提供 IL-12 信号转导，用于配体特异性 IL-2 启动的 NK 细胞为基础的治疗。
