Fibronectin on target cells attenuates natural cytotoxicity of NK cells via myeloid immune checkpoint ILT3/LILRB4/gp49B.

IF 4.8 4区 医学 Q2 IMMUNOLOGY
Fumika Itagaki, Keita Nakatsuka, Haruka Sakai, Shota Endo, Mei-Tzu Su, Toshiyuki Takai
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引用次数: 0

Abstract

Natural killer (NK) cells play pivotal roles in innate immunity as well as in anti-tumor responses via natural killing, while their activity is tightly regulated by cell-surface inhibitory receptors. Immunoglobulin-like transcript 3/leukocyte immunoglobulin-like receptor B4 (ILT3/LILRB4, also known as gp49B in mice) is an inhibitory receptor expressed on activated NK cells as well as myeloid-lineage cells. The common physiologic ligand of human LILRB4 and gp49B was identified very recently as fibronectin, particularly the N-terminal 30 kDa domain (FN30). We hypothesized that LILRB4 could bind fibronectin on target cells in trans together with integrins, classical fibronectin receptors, in cis and deliver an inhibitory signal in NK cells, leading to attenuated natural killing. Flow cytometric and confocal microscopic analyses of NK cell-surface gp49B and integrins suggested that these novel and classical fibronectin receptors, respectively, co-engage fibronectin immobilized on a culture plate. Biochemical analyses indicated that tyrosine phosphorylation of spleen tyrosine kinase was augmented in gp49B-deficient NK cells upon binding to the immobilized fibronectin. While surface fibronectin-poor YAC-1 cells were evenly sensitive as to natural killing of both gp49B-positive and -negative NK cells, the killing of fibronectin-rich Lewis lung carcinoma cells, but not the FN30-knockout cells, was augmented among gp49B-deficient NK cells. These results suggest that the natural cytotoxicity of NK cells is negatively regulated through LILRB4/gp49B sensing fibronectin on target cells, which sheds light on the unexpected role of LILRB4 and fibronectin as a potential attenuator of NK cell cytotoxicity in the tumor microenvironment.

靶细胞上的纤维连接蛋白通过骨髓免疫检查点ILT3/LILRB4/gp49B减弱NK细胞的天然细胞毒性。
NK细胞通过自然杀伤在先天免疫和抗肿瘤反应中发挥关键作用,其活性受到细胞表面抑制受体的严格调控。免疫球蛋白样转录物3/白细胞免疫球蛋白样受体B4 (ILT3/LILRB4,在小鼠中也称为gp49B)是一种抑制受体,在活化的NK细胞和髓系细胞上表达。人类LILRB4和gp49B的共同生理配体是最近才确定的纤维连接蛋白,特别是n端30kda结构域(FN30)。我们假设LILRB4可以反式结合靶细胞上的纤维连接蛋白,与经典的纤维连接蛋白受体整合素顺式结合,并在NK细胞中传递抑制信号,导致自然杀伤减弱。NK细胞表面gp49B和整合素的流式细胞术和共聚焦显微镜分析表明,这些新型和经典的纤维连接蛋白受体分别与固定在培养板上的纤维连接蛋白共接合。生化分析表明,gp49b缺陷NK细胞与固定纤维连接蛋白结合后,脾脏酪氨酸激酶的酪氨酸磷酸化增强。虽然表面纤维连接蛋白缺乏的YAC-1细胞对gp49b阳性和阴性NK细胞的自然杀伤都很敏感,但在gp49b缺乏的NK细胞中,对富含纤维连接蛋白的Lewis肺癌细胞的杀伤能力增强,而对fn30敲除细胞的杀伤能力则没有增强。这些结果表明,NK细胞的天然细胞毒性通过LILRB4/gp49B感知靶细胞上的纤维连接蛋白而受到负调控,这揭示了LILRB4和纤维连接蛋白在肿瘤微环境中作为NK细胞毒性的潜在衰减剂的意想不到的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
International immunology
International immunology 医学-免疫学
CiteScore
9.30
自引率
2.30%
发文量
51
审稿时长
6-12 weeks
期刊介绍: International Immunology is an online only (from Jan 2018) journal that publishes basic research and clinical studies from all areas of immunology and includes research conducted in laboratories throughout the world.
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