KIR2DL5 Can Inhibit Human NK Cell Activation Via Recruitment of Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP-2)1
KIR2DL5 Can Inhibit Human NK Cell Activation Via Recruitment of Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP-2)1
复制标题
KIR2DL5 可通过招募包含 Src 同源区域 2 的蛋白酪氨酸磷酸酶 2 (SHP-2)1 来抑制人 NK 细胞活化
作者：
S. Yusa;Tracey L. Catina;K. Campbell
人类NK细胞使用I类MHC结合抑制性受体，如杀伤细胞Ig样受体（KIR）家族，来区分正常和异常细胞。一些肿瘤和病毒感染的细胞下调I类MHC，从而成为NK细胞的靶点。大量证据表明，KIR介导的抑制机制涉及蛋白质酪氨酸磷酸酶，Src同源2-含有蛋白质酪氨酸磷酸酶-1（SHP-1）和SHP-2，两个磷酸化的细胞质免疫受体酪氨酸基序（ITIM）的招聘。KIR 2DL 5是KIR 2D家族的II型成员，具有非典型胞外域和含有一个典型ITIM和一个非典型ITIM序列的胞浆内结构域。尽管KIR 2DL 5结构由大约50%的人类表达，并且在灵长类物种中是保守的，但其功能尚未确定。在本研究中，我们直接比较了人NK样细胞系中KIR 2DL 5、KIR 3DL 1（具有两个ITIM的I型KIR）和KIR 2DL 4（唯一的另一种II型KIR，具有单个ITIM）的功能和生化特性。我们的研究结果表明，KIR 2DL 5是一个抑制性受体，可以招募SHP-1和SHP-2，其抑制能力更类似于KIR 2DL 4的胞质结构域比KIR 3DL 1。有趣的是，KIR 2DL 5对NK细胞细胞毒性的抑制被显性负性SHP-2阻断，但不被显性负性SHP-1阻断，而两种显性负性磷酸酶都可以阻断KIR 3DL 1的抑制。因此，与I型KIR（3DL 1）相比，II型KIR（2DL 4和2DL 5）的胞质结构域表现出不同的抑制能力，这是由于典型ITIM序列的改变。
Human NK cells use class I MHC-binding inhibitory receptors, such as the killer cell Ig-like receptor (KIR) family, to discriminate between normal and abnormal cells. Some tumors and virus-infected cells down-regulate class I MHC and thereby become targets of NK cells. Substantial evidence indicates that the mechanism of KIR-mediated inhibition involves recruitment of the protein tyrosine phosphatases, Src homology 2-containing protein tyrosine phosphatase-1 (SHP-1) and SHP-2, to two phosphorylated cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs). KIR2DL5 is a type II member of the KIR2D family with an atypical extracellular domain and an intracytoplasmic domain containing one typical ITIM and one atypical ITIM sequence. Although KIR2DL5 structure is expressed by ∼50% of humans and is conserved among primate species, its function has not been determined. In the present study, we directly compared functional and biochemical properties of KIR2DL5, KIR3DL1 (a type I KIR with two ITIMs), and KIR2DL4 (the only other type II KIR, which has a single ITIM) in a human NK-like cell line. Our results show that KIR2DL5 is an inhibitory receptor that can recruit both SHP-1 and SHP-2, and its inhibitory capacity is more similar to that of the cytoplasmic domain of KIR2DL4 than KIR3DL1. Interestingly, inhibition of NK cell cytotoxicity by KIR2DL5 was blocked by dominant-negative SHP-2, but not dominant-negative SHP-1, whereas both dominant-negative phosphatases can block inhibition by KIR3DL1. Therefore, the cytoplasmic domains of type II KIRs (2DL4 and 2DL5) exhibit distinct inhibitory capacities when compared with type I KIRs (3DL1), due to alterations in the canonical ITIM sequences.
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影响因子：
32.4
作者：
Khakoo, SI;Rajalingam, R;Parham, P
通讯作者：
Parham, P
使用痘苗病毒在自然杀伤细胞中进行功能性基因转移。
DOI：
10.1385/1-59259-044-6:265
发表时间：
2000
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Rajagopalan,S;Long,EO
通讯作者：
Long,EO
影响因子：
32.4
作者：
Uhrberg, M;Valiante, NM;Parham, P
通讯作者：
Parham, P
影响因子：
20.3
作者：
J. Sayós;M. Martín;A. Chen;M. Simarro;D. Howie;M. Morra;P. Engel;C. Terhorst
通讯作者：
J. Sayós;M. Martín;A. Chen;M. Simarro;D. Howie;M. Morra;P. Engel;C. Terhorst
影响因子：
4.4
作者：
Say贸s, J;Nguyen, KB;Terhorst, C
通讯作者：
Terhorst, C