Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway
Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway
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DOI：
10.1074/jbc.ra119.011150
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发表时间：
2020-02-21
影响因子：
4.8
通讯作者：
Myers, Linda K.
中科院分区：
文献类型：
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作者：
Park, Jeoung-Eun;Brand, David D.;Myers, Linda K.
多项观察表明 T 细胞失调是类风湿性关节炎发病机制中的一个核心事件。在这里，我们研究了通过抑制性受体白细胞相关免疫球蛋白样受体 1 (LAIR-1) 抑制 T 细胞活化的机制。为了确定 LAIR-1 如何影响 T 细胞受体 (TCR) 信号传导，我们比较了 1) LAIR-1 充足和缺乏小鼠的 T 细胞，2) 表达 LAIR-1 突变体或 C 末端 Src 激酶 (CSK) 突变体的 Jurkat 细胞，以及 3) 来自含有易受化学抑制影响的 CSK 转基因的小鼠的 T 细胞。我们的结果表明，LAIR-1 通过胶原蛋白或补体 C1q（C1Q，包含胶原蛋白样结构域）参与，通过降低经典 T 细胞信号传导途径中关键成分的磷酸化来抑制 TCR 信号传导，包括 LCK 原癌基因 SRC 家族酪氨酸激酶 (LCK)、LYN 原癌基因 SRC 家族酪氨酸激酶 (LYN)、？ T 细胞受体相关蛋白激酶 70 (ZAP-70) 链和三种丝裂原激活蛋白激酶（细胞外信号调节激酶、c-Jun N 末端激酶 1/2 和 p38）。 LAIR-1 的胞内区域包含两个基于免疫受体酪氨酸的抑制基序，它们均被 LAIR-1 激活磷酸化，免疫沉淀实验表明 LAIR-1 中的 Tyr-251 与 CSK 结合。使用 CRISPR/Cas9 介导的基因组编辑，我们证明 CSK 对于 LAIR-1 诱导的人类 TCR 信号转导抑制至关重要。来自表达 PP1 类似物敏感形式的 CSK (CskAS) 的小鼠 T 细胞证实了这些发现，我们还发现 Tyr-251 对于 LAIR-1 的抑制功能至关重要。我们认为 LAIR-1 激活可能是控制炎症的一种策略，并可能为控制自身免疫性疾病提供潜在的治疗方法。
Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1?sufficient and ?deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition. Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q, which contains a collagen-like domain) inhibits TCR signaling by decreasing the phosphorylation of key components in the canonical T-cell signaling pathway, including LCK proto-oncogene SRC family tyrosine kinase (LCK), LYN proto-oncogene SRC family tyrosine kinase (LYN), ? chain of T-cell receptor?associated protein kinase 70 (ZAP-70), and three mitogen-activated protein kinases (extracellular signal?regulated kinase, c-Jun N-terminal kinase 1/2, and p38). The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments revealed that Tyr-251 in LAIR-1 binds CSK. Using CRISPR/Cas9-mediated genome editing, we demonstrate that CSK is essential for the LAIR-1?induced inhibition of the human TCR signal transduction. T cells from mice that expressed a PP1 analog?sensitive form of CSK (CskAS) corroborated these findings, and we also found that Tyr-251 is critical for LAIR-1's inhibitory function. We propose that LAIR-1 activation may be a strategy for controlling inflammation and may offer a potential therapeutic approach for managing autoimmune diseases.