文章基本信息

标题：Intracellular osteopontin regulates homeostasis and function of natural killer cells
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作者：Jianmei W. Leavenworth ; Bert Verbinnen ; Qin Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：2
页码：494-499
DOI：10.1073/pnas.1423011112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMaintenance of a pool of natural killer (NK) cells with optimal immune function is crucial for host defense against pathogens or cancerous tumor formation. Here we identify intracellular osteopontin (OPN-i) as an essential molecular component responsible for maintenance of functional NK cell expansion. Absence of OPN-i results in failure to maintain normal NK cellularity and increased cell death following stimulation by cytokine interleukin-15. OPN-deficient NK cells fail to successfully navigate the contraction phase of the immune response, resulting in impaired expansion of long-lived NK cells and defective responses to viral infection and tumor cells. Insight into the contribution of OPN-i to NK cell responses may provide the basis for improved approaches to immunotherapy for infectious disease and cancer. Natural killer (NK) cells play an essential role in the immune response to infection and cancer. After infection or during homeostatic expansion NK cells express a developmental program that includes a contraction phase followed by the formation of long-lived mature memory-like cells. Although this NK cell response pattern is well established, the underlying mechanisms that ensure efficient transition to long-lived NK cells remain largely undefined. Here we report that deficient expression of intracellular osteopontin (OPN-i) by NK cells results in defective responses to IL-15 associated with a substantial increase in the NK cell contraction phase of homeostatic expansion, defective expression of the Eomes transcription factor, and diminished responses to metastatic tumors. The OPN-i-deficient phenotype is accompanied by increased NK cell apoptosis, impaired transition from immature to mature NK cells, and diminished ability to develop memory-like NK cells that respond to mouse cytomegalovirus. Gene pathway analysis of OPN-i-deficient NK cells suggests that the mechanistic target of rapamycin pathway may connect OPN-i to Eomes and T-bet expression by mature NK cells following up-regulation of OPN-i after IL-15 stimulation. Identification of OPN-i as an essential molecular component for maintenance of functional NK cell expansion provides insight into the NK cell response and may provide the basis for improved approaches to immunotherapy for infectious disease and cancer.
关键词：cellular maintenance ; contraction ; long-lived cell ; memory cell ; T-box transcription factor