Engels Niklas, König Lars M, Schulze Wiebke, Radtke Daniel, Vanshylla Kanika, Lutz Johannes, Winkler Thomas H, Nitschke Lars, Wienands Jürgen
Institute of Cellular and Molecular Immunology, Georg-August-University of Göttingen, Medical Faculty, Humboldtallee 34, 37073 Göttingen, Germany.
Chair of Genetics, Department of Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Staudtstrasse 5, 91058 Erlangen, Germany.
Nat Commun. 2014 Nov 21;5:5456. doi: 10.1038/ncomms6456.
The vigorous response of IgG-switched memory B cells to recurring pathogens involves enhanced signalling from their B-cell antigen receptors (BCRs). However, the molecular signal amplification mechanisms of memory-type BCRs remained unclear. Here, we identify the immunoglobulin tail tyrosine (ITT) motif in the cytoplasmic segments of membrane-bound IgGs (mIgGs) as the principle signal amplification device of memory-type BCRs in higher vertebrates and decipher its signalling microanatomy. We show that different families of protein tyrosine kinases act upstream and downstream of the ITT. Spleen tyrosine kinase (Syk) activity is required for ITT phosphorylation followed by recruitment of the adaptor protein Grb2 into the mIgG-BCR signalosome. Grb2 in turn recruits Bruton's tyrosine kinase (Btk) to amplify BCR-induced Ca(2+) mobilization. This molecular interplay of kinases and adaptors increases the antigen sensitivity of memory-type BCRs, which provides a cell-intrinsic trigger mechanism for the rapid reactivation of IgG-switched memory B cells on antigen recall.
IgG 类别转换记忆 B 细胞对反复出现的病原体的强烈反应涉及来自其 B 细胞抗原受体（BCR）的增强信号传导。然而，记忆型 BCR 的分子信号放大机制仍不清楚。在这里，我们确定膜结合 IgG（mIgG）胞质段中的免疫球蛋白尾部酪氨酸（ITT）基序是高等脊椎动物记忆型 BCR 的主要信号放大装置，并解析其信号微解剖结构。我们表明，不同家族的蛋白酪氨酸激酶在 ITT 的上游和下游起作用。脾酪氨酸激酶（Syk）活性是 ITT 磷酸化所必需的，随后衔接蛋白 Grb2 被招募到 mIgG-BCR 信号体中。Grb2 进而招募布鲁顿酪氨酸激酶（Btk）以放大 BCR 诱导的 Ca(2+)动员。激酶和衔接蛋白的这种分子相互作用增加了记忆型 BCR 的抗原敏感性，这为 IgG 类别转换记忆 B 细胞在抗原再次接触时的快速重新激活提供了一种细胞内在触发机制。
