2B4 (CD244)-mediated activation of cytotoxicity and IFN-γ release in human NK cells involves distinct pathways
2B4 (CD244)-mediated activation of cytotoxicity and IFN-γ release in human NK cells involves distinct pathways
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DOI：
10.4049/jimmunol.167.11.6210
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发表时间：
2001-12-01
影响因子：
4.4
通讯作者：
Mathew, PA
中科院分区：
文献类型：
--
作者：
Chuang, SS;Kumaresan, PR;Mathew, PA
2B4（CD244）是免疫球蛋白超家族受体CD2亚群的成员，在所有人类自然杀伤（NK）细胞、一部分T细胞、嗜碱性粒细胞和单核细胞上表达。2B4激活NK细胞介导的细胞毒性，诱导干扰素 - γ和基质金属蛋白酶的分泌以及NK细胞的侵袭性。尽管已有几种分子显示与2B4相互作用，但2B4介导的NK细胞激活的信号传导机制仍然未知。在本研究中，我们发现2B4在YT细胞（一种人类NK细胞系）上的交联导致激活蛋白 - 1（AP - 1）的DNA结合活性增加，AP - 1是白细胞中核基因表达的重要调节因子。我们研究了各种可能通过2B4参与激活YT细胞裂解功能的信号分子的可能作用。用各种特异性抑制剂处理YT细胞表明，2B4对YT细胞在自发性和抗体依赖性细胞毒性中的刺激是Ras/Raf依赖性的，并涉及多个丝裂原活化蛋白激酶（MAPK）信号通路（ERK1/2和p38）。然而，只有转录抑制剂和p38抑制剂抑制2B4介导的干扰素 - γ释放，这表明细胞毒性和细胞因子释放涉及不同的通路。在本研究中我们还表明，2B4与T细胞活化连接蛋白（LAT）组成性结合，并且2B4可能通过一种LAT依赖性信号通路介导NK细胞的激活。这些结果表明，2B4介导的NK细胞激活涉及包括LAT、Ras、Raf、ERK和p38的复杂相互作用，并且细胞溶解功能和细胞因子产生可能由不同的通路调节。
2B4 (CD244), a member of the CD2 subset of the Ig superfamily receptors, is expressed on all human NK cells, a subpopulation of T cells, basophils and monocytes. 2B4 activates NK cell mediated cytotoxicity, induces secretion of IFN-T and matrix metalloproteinases, and NK cell invasiveness. Although there has been several molecules shown to interact with 2B4, the signaling mechanism of 2B4-mediated activation of NK cells is still unknown. In this study, we found cross-linking of 2B4 on YT cells, a human NK cell line, results in the increased DNA binding activity of activator protein-1 (AP-1), an important regulator of nuclear gene expression in leukocytes. We investigated the possible role of various signaling molecules that may be involved in the activation of lytic function of YT cells via 2B4. Treatment of YT cells with various specific inhibitors indicate that 2B4-stimulation of YT cells in spontaneous and Ab-dependent cytotoxicity is Ras/Raf dependent and involves multiple MAPK signaling pathways (ERK1/2 and p38). However, only inhibitors of transcription and p38 inhibited 2B4-mediated IFN-gamma release indicating distinct pathways are involved in cytotoxicity and cytokine release. In this study we also show that 2B4 constitutively associates with the linker for activation of T cells (LAT) and that 2B4 may mediate NK cell activation via a LAT-dependent signaling pathway. These results indicate that 2B4-mediated activation of NK cells involves complex interactions involving LAT, Ras, Raf, ERK and p38 and that cytolytic function and cytokine production may be regulated by distinct pathways.