Abundant CpG-sequences in human genomes inhibit KIR3DL2-expressing NK cells.
Abundant CpG-sequences in human genomes inhibit KIR3DL2-expressing NK cells.
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作者：
Pugh J;Guethlein L;Parham P
杀伤免疫球蛋白样受体（KIR）包括主要由自然杀伤（NK）细胞表达的细胞表面糖蛋白的多样性、高度多态性家族。这些先天免疫淋巴细胞在人类生殖和对病毒感染的免疫应答中发挥重要作用。KIR 3DL 2是一种抑制性NK细胞受体，其识别主要组织相容性复合体的HLA-A3和HLA-A11 I类糖蛋白的共同表位。KIR 3DL 2还结合含有CpG基序的外源DNA。这种相互作用导致KIR-DNA的内化。外源性CpG-DNA通常激活NK细胞，但KIR 3DL 2-DNA结合和内化的特异性尚不清楚。我们假设KIR 3DL 2以区分病原体DNA和自身DNA的序列特异性方式结合外源DNA。为了验证这一假设，我们调查了人类基因组中的八聚体CpG-DNA序列，以及所有细菌、真菌、病毒和寄生虫的参考基因组中的八聚体CpG-DNA序列，重点是医学相关物种。在所有病原体中，感染人类的寄生蠕虫基因组中CpG基序侧翼的核苷酸与人类基因组中的核苷酸最不同。我们用人类或病原体基因组中最常见的CpG-DNA序列培养KIR 3DL 2 +NKL细胞。DNA摄取与人类基因组中最常见的CpG-DNA序列呈负相关。这些CpG-DNA序列在KIR 3DL 2 +NKL细胞中诱导抑制性信号传导。相比之下，KIR 3DL 2 +NKL细胞在与寄生蠕虫普遍存在的CpG-DNA序列一起培养后裂解更多的恶性靶标并产生更多的IFNγ。通过将功能免疫学应用于进化基因组学，我们得出结论，KIR 3DL 2允许NK细胞将自身DNA与病原体DNA区分开。
Killer Immunoglobulin-like Receptors (KIR) comprise a diverse, highly polymorphic family of cell-surface glycoproteins that are principally expressed by Natural Killer (NK) cells. These innate immune lymphocytes fulfill vital functions in human reproduction and immune responses to viral infection. KIR3DL2 is an inhibitory NK cell receptor that recognizes a common epitope of the HLA-A3 and HLA-A11 class I glycoproteins of the major histocompatibility complex. KIR3DL2 also binds exogenous DNA containing the CpG motif. This interaction causes internalization of the KIR-DNA. Exogenous CpG-DNA typically activates NK cells, but the specificity of KIR3DL2-DNA binding and internalization is unclear. We hypothesized that KIR3DL2 binds exogenous DNA in a sequence-specific manner that differentiates pathogen DNA from self-DNA. In testing this hypothesis, we surveyed octameric CpG-DNA sequences in the human genome, and in reference genomes of all bacteria, fungi, viruses, and parasites, with focus on medically relevant species. Among all pathogens, the nucleotides flanking CpG motifs in the genomes of parasitic worms that infect humans are most divergent from those in the human genome. We cultured KIR3DL2+NKL cells with the commonest CpG-DNA sequences in either human or pathogen genomes. DNA uptake was negatively correlated with the most common CpG-DNA sequences in the human genome. These CpG-DNA sequences induced inhibitory signaling in KIR3DL2+NKL cells. In contrast, KIR3DL2+NKL cells lysed more malignant targets and produced more IFNγ after culture with CpG-DNA sequences prevalent in parasitic worms. By applying functional immunology to evolutionary genomics, we conclude that KIR3DL2 allows NK cells to differentiate self-DNA from pathogen DNA.
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影响因子：
16.6
作者：
Pohar J;Lainšček D;Ivičak-Kocjan K;Cajnko MM;Jerala R;Benčina M
通讯作者：
Benčina M
影响因子：
5.4
作者：
Fearon, K;Marshall, JD;Coffman, RL
通讯作者：
Coffman, RL
影响因子：
14.9
作者：
BIRD, AP
通讯作者：
BIRD, AP
影响因子：
18.2
作者：
Lacroix, Aurelie;Vengut-Climent, Empar;Sleiman, Hanadi F.
通讯作者：
Sleiman, Hanadi F.
DOI：
10.1084/jem.184.2.505
发表时间：
1996-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pende D;Biassoni R;Cantoni C;Verdiani S;Falco M;di Donato C;Accame L;Bottino C;Moretta A;Moretta L
通讯作者：
Moretta L