Institute of Immunology, University Medical Center Hamburg Eppendorf (UKE), Hamburg, Germany.
Department Virus Immunology, Leibniz Institute of Virology (LIV), Hamburg, Germany.
Front Immunol. 2023 Dec 15;14:1277967. doi: 10.3389/fimmu.2023.1277967. eCollection 2023.
Natural killer (NK) cells are important antiviral effector cells and also involved in tumor clearance. NK cells express IFNAR, rendering them responsive to Type I IFNs. To evaluate Type I IFN-mediated modulation of NK cell functions, individual Type I IFNs subtypes were assessed for their ability to activate NK cells. Different Type I IFN subtypes displayed a broad range in the capacity to induce and modulate NK cell activation and degranulation, measured by CD69 and CD107a expression in response to leukemia cell line K562. When including biological sex as a variable in the analysis, transwell co-cultures of NK cells with either male- or female-derived PBMCs or pDCs stimulated with the TLR7/8 agonist CL097 showed that NK cells were more activated by CL097-stimulated cells derived from females. These sex-specific differences were linked to higher CL097-induced IFNα production by pDCs derived from females, indicating an extrinsic sex-specific effect of Type I IFNs on NK cell function. Interestingly, in addition to the extrinsic effect, we also observed NK cell-intrinsic sex differences, as female NK cells displayed higher activation levels after IFNα-stimulation and after co-culture with CL097-stimulated pDCs, suggesting higher activation of IFNα-signaling transduction in female NK cells. Taken together, the results from these studies identify both extrinsic and intrinsic sex-specific differences in Type I IFN-dependent NK cell functions, contributing to a better understanding of sex-specific differences in innate immunity.
自然杀伤 (NK) 细胞是重要的抗病毒效应细胞，也参与肿瘤清除。NK 细胞表达 IFNAR，使其对 I 型干扰素敏感。为了评估 I 型干扰素对 NK 细胞功能的调节作用，评估了各个 I 型干扰素亚型激活 NK 细胞的能力。不同的 I 型干扰素亚型在诱导和调节 NK 细胞激活和脱颗粒的能力方面表现出广泛的差异，这可以通过 CD69 和 CD107a 的表达来衡量，以响应白血病细胞系 K562。当将生物学性别作为分析中的一个变量时，NK 细胞与来自男性或女性的 PBMC 或用 TLR7/8 激动剂 CL097 刺激的 pDC 的 Transwell 共培养显示，NK 细胞被来自女性的 CL097 刺激的细胞激活得更多。这些性别特异性差异与来自女性的 pDC 产生的更高的 CL097 诱导的 IFNα有关，表明 I 型干扰素对 NK 细胞功能的外在性别特异性影响。有趣的是，除了外在效应外，我们还观察到 NK 细胞内在的性别差异，因为女性 NK 细胞在 IFNα刺激后和与 CL097 刺激的 pDC 共培养后显示出更高的激活水平，这表明女性 NK 细胞中 IFNα 信号转导的更高激活。总之，这些研究的结果确定了 I 型干扰素依赖性 NK 细胞功能中的外在和内在性别特异性差异，有助于更好地理解先天免疫中的性别特异性差异。
