Expansion of an atypical NK cell subset in mouse models of systemic lupus erythematosus.
Expansion of an atypical NK cell subset in mouse models of systemic lupus erythematosus.
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DOI：
10.4049/jimmunol.1402673
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发表时间：
2015-02-15
期刊：
影响因子：
--
通讯作者：
Bolland S
中科院分区：
文献类型：
--
作者：
Voynova EN;Skinner J;Bolland S
慢性炎症，如自身免疫性疾病，可以扰乱免疫细胞稳态，诱导通常罕见的细胞群扩张。在我们对各种狼疮小鼠模型的分析中，我们发现一个不常见的子集NK1.1+CD11c+CD122+MHC-II+的频率增加。这些细胞与NK细胞谱系和先前描述为ikdc的细胞具有相同的特征：它们依赖于IL15并表达E4BP4；它们具有细胞毒性，激活后产生I型和II型干扰素；通过MHC-II表达和cd8交叉呈递，它们都是有效的抗原呈递细胞。这些非典型NK细胞对TLR刺激有反应，因此在Tlr7基因拷贝数高的小鼠中数量最多。通过体内BrdU掺入评估，它们具有高度增殖性。在过继性迁移实验中，它们的高数量持续数月，并保持其表面标记剖面，表明该种群发育稳定。mRNA和microrna的基因表达分析显示，细胞周期程序发生了改变，其中miR15/16家族成员的表达上调，这可能是生长因子、Ras和E2F活性水平升高介导的增殖信号的结果。另一方面，这些细胞中miR150、miR181和miR744的低表达意味着它们的分化能力降低。这些结果表明，NK谱系的细胞在受到TLR刺激后可能会开启增殖程序，不利于它们完全分化为成熟的NK细胞。
Chronic inflammatory conditions, such as in autoimmune disease, can disturb immune cell homeostasis and induce the expansion of normally rare cell populations. In our analysis of various murine models of lupus, we detect increased frequency of an uncommon subset identified as NK1.1+CD11c+CD122+MHC-II+. These cells share characteristics with the NK cell lineage and with cells previously described as IKDCs: they depend on IL15 and express E4BP4; they are cytotoxic and produce type I and type II interferon upon activation; they are efficient antigen presenting cells both through MHC-II expression and in cross-presentation to CD8s. These atypical NK cells are responsive to TLR stimulation and thus are most abundant in mice with high copy number of the Tlr7 gene. They are highly proliferative as assessed by in vivo BrdU incorporation. In adoptive transfer experiments they persist in high numbers for months and maintain their surface marker profile, indicating that this population is developmentally stable. Gene expression analyses on both mRNA and microRNAs show a modified cell cycle program in which various miR15/16 family members are upregulated, presumably as a consequence of the proliferative signal mediated by the increased level of growth factors, Ras and E2F activity. On the other hand, low expression of miR150, miR181 and miR744 in these cells implies a reduction in their differentiation capacity. These results suggest that cells of the NK lineage that undergo TLR stimulation might turn on a proliferative program in detriment of their full differentiation into mature NK cells.
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