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标题：Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Rα complexes
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作者：Kutlu G. Elpek ; Mark P. Rubinstein ; Angelique Bellemare-Pelletier 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：2010
卷号：107
期号：50
页码：21647-21652
DOI：10.1073/pnas.1012128107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Cytotoxic lymphocytes such as natural killer (NK) and CD8 T cells play important roles in immunosurveillance by killing virally infected or malignant cells. The homeostatic cytokine, IL-15, promotes the development, function, and survival of NK and CD8 T cells. IL-15 is normally presented in trans as a surface complex with IL-15 receptor-alpha-chain (IL-15R) by dendritic cells (DCs) and monocytes. Signaling by IL-15 occurs via the IL-2/IL-15 receptor {beta}-chain (CD122) which is expressed primarily by NK1.1+ cells and CD8 T cells. The use of preformed complexes of IL-15 with soluble IL-15R complexes to boost the effector function of CD122+ cytolytic lymphocytes such as NK and CD8 T cells has recently gained considerable attention. Here we describe the impact of transient and prolonged in vivo stimulation by IL-15/IL-15R complexes on NK and CD8 T cells. Whereas transitory stimulation increased the number of activated NK cells and significantly enhanced their effector function, prolonged stimulation by IL-15/IL-15R complexes led to a marked accumulation of mature NK cells with considerably impaired activation, cytotoxicity, and proliferative activity, and an altered balance of activating and inhibitory receptors. In contrast to NK cells, CD8 T cells exhibited an activated phenotype and robust T cell receptor stimulation and effector function upon chronic stimulation with IL-15/IL-15R complexes. Thus, prolonged stimulation with the strong activating signal leads to a preferential accrual of mature NK cells with altered activation and diminished functional capacity. These findings point to a negative feedback mechanism to preferentially counterbalance excessive NK cell activity and may have important implications for cytokine immunotherapy.
关键词：cytokine complexes ; natural killer cell dysfunction ; end-stage cells