Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143.
Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA 94143.
J Immunol. 2019 Aug 15;203(4):981-989. doi: 10.4049/jimmunol.1900396. Epub 2019 Jul 12.
NK cells are innate lymphocytes that play an integral role in tumor rejection and viral clearance. Unlike their other lymphocyte counterparts, NK cells have the unique ability to recognize and lyse target cells without prior exposure. However, there are no known NK cell-specific genes that are exclusively expressed by all NK cells. Therefore, identification of NK cell-specific genes would allow a better understanding of why NK cells are unique cytotoxic lymphocytes. From the Immunological Genome (ImmGen) Consortium studies, we identified kruppel-like factor 12 (), encoding a novel transcription factor, preferentially expressed in C57BL/6 mouse NK cells. KLF12 was dispensable for NK cell development, IFN-γ production, degranulation, and proliferation in knockout mice. RNA-sequencing analysis revealed increased expression of , an antiproliferative gene, in KLF12-deficient NK cells compared with wild-type NK cells. Interestingly, competitive mixed bone marrow chimeric mice exhibited reduced development of KLF12-deficient NK cells, altered IFN-γ production and degranulation, and impairment of NK cell proliferation in vitro and in vivo in response to mouse CMV infection. KLF12-deficient NK cells from bone marrow chimeric mice also expressed higher levels of the IL-21R, which resulted in increased IL-21R signaling and correlated with greater inhibition of NK cell proliferation. Furthermore, IL-21 induced expression, which correlated with arrested NK cell maturation and proliferation. In summary, we found that KLF12 regulates mouse NK cell proliferation potentially by regulating expression of via IL-21.
自然杀伤 (NK) 细胞是先天淋巴细胞，在肿瘤排斥和病毒清除中发挥着重要作用。与其他淋巴细胞不同，NK 细胞具有独特的识别和裂解靶细胞的能力，而无需预先暴露。然而，目前还没有已知的 NK 细胞特异性基因，这些基因是所有 NK 细胞所特有的。因此，鉴定 NK 细胞特异性基因将有助于更好地理解为什么 NK 细胞是独特的细胞毒性淋巴细胞。从免疫基因组 (ImmGen) 联盟的研究中，我们鉴定了 kruppel 样因子 12 (KLF12)，它编码一种新型转录因子，在 C57BL/6 小鼠 NK 细胞中优先表达。KLF12 对于 NK 细胞的发育、IFN-γ 的产生、脱颗粒和增殖在 基因敲除小鼠中是可有可无的。RNA 测序分析显示，与野生型 NK 细胞相比，KLF12 缺陷型 NK 细胞中增殖抑制基因 的表达增加。有趣的是，竞争混合骨髓嵌合小鼠表现出 KLF12 缺陷型 NK 细胞发育减少、IFN-γ 产生和脱颗粒改变以及对小鼠 CMV 感染的 NK 细胞增殖体外和体内受损。来自骨髓嵌合小鼠的 KLF12 缺陷型 NK 细胞也表达更高水平的 IL-21R，这导致 IL-21R 信号增加，并与 NK 细胞增殖的更大抑制相关。此外，IL-21 诱导 的表达，这与 NK 细胞成熟和增殖的停滞相关。总之，我们发现 KLF12 通过调节 IL-21 诱导的 的表达来调节小鼠 NK 细胞的增殖。
