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自身免疫疾病易感性基因抑制 YTS NK 细胞系和敲除小鼠的 NK 细胞功能。

The Autoimmune Disorder Susceptibility Gene Restrains NK Cell Function in YTS NK Cell Line and Knockout Mice.

机构信息

The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, United States.

Section of Immunology, Allergy, and Rheumatology, Department of Pediatric Medicine, Texas Children's Hospital, Houston, TX, United States.

出版信息

Front Immunol. 2019 Feb 1;10:68. doi: 10.3389/fimmu.2019.00068. eCollection 2019.

DOI:10.3389/fimmu.2019.00068
PMID:30774629
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6367972/
Abstract

locus polymorphisms have been associated with several autoimmune diseases. We overexpressed in YTS natural killer (NK) cells and observed reduced NK cell cytotoxicity and IFN-γ release, delayed dendritic cell (DC) maturation, decreased conjugate formation, cell-surface receptor downregulation and increased autophagy. In contrast, siRNA mediated knockdown resulted in increased NK cell cytotoxicity, reversal of receptor expression and disrupted mitophagy. Subcellular localization studies demonstrated that CLEC16A is a cytosolic protein that associates with Vps16A, a subunit of class C Vps-HOPS complex, and modulates receptor expression via autophagy. knockout (KO) in mice resulted in altered immune cell populations, increased splenic NK cell cytotoxicity, imbalance of dendritic cell subsets, altered receptor expression, upregulated cytokine and chemokine secretion. Taken together, our findings indicate that CLEC16A restrains secretory functions including cytokine release and cytotoxicity and that a delicate balance of CLEC16A is needed for NK cell function and homeostasis.

摘要

基因座多态性与多种自身免疫性疾病有关。我们在 YTS 自然杀伤 (NK) 细胞中过表达 CLEC16A，并观察到 NK 细胞的细胞毒性和 IFN-γ 释放减少，树突状细胞 (DC) 成熟延迟，共轭形成减少，细胞表面受体下调和自噬增加。相比之下，siRNA 介导的敲低导致 NK 细胞的细胞毒性增加，受体表达逆转和线粒体自噬被破坏。亚细胞定位研究表明，CLEC16A 是一种胞质蛋白，与 Vps16A 结合，Vps16A 是 C 类 Vps-HOPS 复合物的一个亚基，通过自噬调节受体表达。在小鼠中敲除 (KO) 导致免疫细胞群改变，脾 NK 细胞细胞毒性增加，树突状细胞亚群失衡，受体表达改变，细胞因子和趋化因子分泌上调。总之，我们的研究结果表明，CLEC16A 抑制包括细胞因子释放和细胞毒性在内的分泌功能，NK 细胞的功能和稳态需要 CLEC16A 的精细平衡。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/295f5a8e00fc/fimmu-10-00068-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/3dee1981b50e/fimmu-10-00068-g0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/130761a18e55/fimmu-10-00068-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/2ca665e319ca/fimmu-10-00068-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/295f5a8e00fc/fimmu-10-00068-g0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/3dee1981b50e/fimmu-10-00068-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/3939c7ea9dd3/fimmu-10-00068-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/2f65c4d93002/fimmu-10-00068-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/5f8617db20da/fimmu-10-00068-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/130761a18e55/fimmu-10-00068-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/2ca665e319ca/fimmu-10-00068-g0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0898/6367972/295f5a8e00fc/fimmu-10-00068-g0007.jpg

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