Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.
Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.
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DOI：
10.1084/jem.20150388
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发表时间：
2015-12-14
期刊：
影响因子：
--
通讯作者：
Kane LP
中科院分区：
文献类型：
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作者：
Phong BL;Avery L;Sumpter TL;Gorman JV;Watkins SC;Colgan JD;Kane LP
Phong等人表明，根据p-Lyn的表达，抗原对肥大细胞的活化可导致对肥大细胞功能和信号传导的二分效应，这可通过Tim-3连接来加强。T细胞（或跨膜）免疫球蛋白和粘蛋白结构域蛋白3（Tim-3）作为慢性刺激的、通常功能失调的T细胞上的新型免疫检查点受体（ICR）引起了显著的关注。Tim-3的抗体可以增强抗病毒和抗肿瘤免疫应答。Tim-3也由肥大细胞、NK细胞和巨噬细胞和树突细胞的特定亚群组成性表达。有充分的证据表明Tim-3在这些后一种细胞类型中具有积极作用，这与Tim-3作为T细胞抑制分子的模型不一致。目前，人们对Tim-3调节T细胞或其他细胞类型功能的分子机制知之甚少。我们重点研究了Tim-3连接对肥大细胞活化的影响，因为这些细胞组成性表达Tim-3，并通过含有ITAM的IgE受体（Fc ε RI）激活，使用类似于T细胞中的信号传导途径。使用各种功能获得和功能丧失方法，我们发现Tim-3在受体近端点起作用，以增强林恩激酶依赖性信号传导途径，该途径调节Fc ε RI连接下游的立即相脱粒和晚期细胞因子产生。
Phong et al. show that depending on the expression of p-Lyn, mast cell activation by antigen can result in dichotomous effects on mast cell function and signaling that can be accentuated by Tim-3 ligation. T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.