CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling
CD22 ligand-binding and signaling domains reciprocally regulate B-cell Ca2+ signaling
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DOI：
10.1073/pnas.1304888110
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发表时间：
2013-07-23
影响因子：
11.1
通讯作者：
Nitschke, Lars
中科院分区：
文献类型：
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作者：
Mueller, Jennifer;Obermeier, Ingrid;Nitschke, Lars
很高比例的人类B细胞携带具有自身反应性的B细胞受体(BCR)。CD22等抑制性受体可下调自身反应性BCR反应。CD22的胞外区与唾液酸在顺式或反式的顺式或反式结合。唾液酸是一种自身配体，因为它们在脊椎动物中含量丰富，但通常不被病原体表达。我们发现，CD22的顺式配体结合通过控制CD22与BCR的结合，对于调节B细胞的钙信号是至关重要的。CD22的CD22配体结合域突变的小鼠表现出强烈的钙信号减弱。相比之下，CD22免疫受体酪氨酸抑制基序突变的小鼠增加了B细胞的钙反应，增加了B细胞的周转率，并损害了B细胞的存活。因此，CD22配体结合区在调节BCR信号通路中起着至关重要的作用，而BCR信号通路与控制自身免疫有关。
A high proportion of human B cells carry B-cell receptors (BCRs) that are autoreactive. Inhibitory receptors such as CD22 can down-modulate autoreactive BCR responses. With its extracellular domain, CD22 binds to sialic acids in alpha 2,6 linkages in cis, on the surface of the same B cell or in trans, on other cells. Sialic acids are self ligands, as they are abundant in vertebrates, but are usually not expressed by pathogens. We show that cis-ligand binding of CD22 is crucial for the regulation of B-cell Ca2+ signaling by controlling the CD22 association to the BCR. Mice with a mutated CD22 ligand-binding domain of CD22 showed strongly reduced Ca2+ signaling. In contrast, mice with mutated CD22 immunoreceptor tyrosine-based inhibition motifs have increased B-cell Ca2+ responses, increased B-cell turnover, and impaired survival of the B cells. Thus, the CD22 ligand-binding domain has a crucial function in regulating BCR signaling, which is relevant for controlling autoimmunity.