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), ζ 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.

中文翻译：

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白细胞相关的免疫球蛋白样受体1通过减少T细胞信号传导途径中的蛋白质磷酸化来抑制T细胞信号传导。

多种观察表明，T细胞失调是类风湿关节炎发病机制中的重要事件。在这里，我们研究了通过抑制性受体白细胞相关的免疫球蛋白样受体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）来自LAIR-1充足和不足的小鼠的T细胞，2）表达LAIR-1突变体或C末端Src激酶的Jurkat细胞（ CSK）突变体，以及3）来自小鼠的T细胞，其中含有易受化学抑制作用的CSK转基因。我们的结果表明，胶原蛋白或补体C1q（C1Q，其中包含胶原样结构域）与LAIR-1的结合可通过降低规范性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）的ζ链和三种促分裂原激活蛋白激酶（细胞外信号调节激酶，c-Jun N端激酶1/2和p38）。LAIR-1的细胞内区域含有两个基于免疫受体酪氨酸的抑制基序，它们均通过LAIR-1激活而被磷酸化，并且免疫沉淀实验表明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TCR信号转导抑制至关重要。表达PP1类似物敏感性CSK（CskAS）的小鼠T细胞证实了这些发现，我们还发现Tyr-251对LAIR-1'至关重要 抑制功能。我们提出，LAIR-1激活可能是控制炎症的策略，并可能为管理自身免疫性疾病提供潜在的治疗方法。