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PNAS:III型干扰素助力NK细胞发挥最佳活性

来源:生物谷 2015-05-12 10:06

                                                                       

2015年5月12日讯 /生物谷BIOON/ --近日, 来自澳大利亚的科学家在国际学术期刊PNAS发表了一项最新研究进展,他们利用敲除小鼠模型发现III型干扰素对NK细胞发挥效应功能具有重要调节作用。
 
自然杀伤细胞是正常情况下存在于循环系统中的固有淋巴细胞,具有对抗肿瘤起始转移,促进炎症过程中免疫系统功能执行的作用。到目前为止,虽然关于I型干扰素在NK细胞功能发挥方面的重要功能已经得到大量研究,但促进NK细胞功能发挥的信号仍没有完全了解,特别是III型干扰素在NK细胞功能发挥方面的作用仍研究较少。
 
在该项研究中,研究人员利用III型干扰素IL-28的受体缺失小鼠--IL-28R缺失小鼠进行了相关研究,IL-28R缺失还会导致III型干扰素IFN-λ信号不能正常传递,结果发现IL-28R缺失会导致小鼠抵抗LPS和盲肠结扎穿刺诱导的感染性休克,并且IL-28R缺失会造成这些疾病模型中特征性细胞因子的紊乱失调。
 
同时,相比于野生型小鼠,IL-28R缺失小鼠更易于发生实验性肿瘤转移和致癌物质诱导的肿瘤形成,在此基础上阻断干扰素α/β受体1(IFNAR1)会进一步增强肿瘤转移和肿瘤发育。除此之外,研究人员还发现IL-28缺失小鼠易于形成NK细胞敏感性淋巴瘤。在NK细胞中特异性敲除IL-28R,再将这群细胞转移到淋巴细胞缺陷小鼠体内,这会导致LPS诱导的干扰素γ表达水平下降,同时能够增强肿瘤转移。
 
综上所述,该研究利用IL-28R缺失小鼠,首次发现III型干扰素IFN-λ能够直接调节体内NK细胞发挥效应功能,对于研究NK细胞体内调控机制具有重要意义。(生物谷Bioon.com)
 
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NK cells require IL-28R for optimal in vivo activity
 
Fernando Souza-Fonseca-Guimaraesa,b, Arabella Younga,b, Deepak Mittala, Ludovic Martineta, Claudia Bruedigamc, Kazuyoshi Takedad, Christopher E. Andonioue, Mariapia A. Degli-Espostie, Geoffrey R. Hillf,g, and Mark J. Smyth
 
Natural killer (NK) cells are naturally circulating innate lymphoid cells that protect against tumor initiation and metastasis and contribute to immunopathology during inflammation. The signals that prime NK cells are not completely understood, and, although the importance of IFN type I is well recognized, the role of type III IFN is comparatively very poorly studied. IL-28R-deficient mice were resistant to LPS and cecal ligation puncture-induced septic shock, and hallmark cytokines in these disease models were dysregulated in the absence of IL-28R. IL-28R-deficient mice were more sensitive to experimental tumor metastasis and carcinogen-induced tumor formation than WT mice, and additional blockade of interferon alpha/beta receptor 1 (IFNAR1), but not IFN-γ, further enhanced metastasis and tumor development. IL-28R-deficient mice were also more susceptible to growth of the NK cell-sensitive lymphoma, RMAs. Specific loss of IL-28R in NK cells transferred into lymphocyte-deficient mice resulted in reduced LPS-induced IFN-γ levels and enhanced tumor metastasis. Therefore, by using IL-28R-deficient mice, which are unable to signal type III IFN-λ, we demonstrate for the first time, to our knowledge, the ability of IFN-λ to directly regulate NK cell effector functions in vivo, alone and in the context of IFN-αβ.
 
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