Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection.
Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection.
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DOI：
10.1016/j.immuni.2016.09.012
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发表时间：
2016-10-18
期刊：
影响因子：
32.4
通讯作者：
Sancho, David
中科院分区：
文献类型：
--
作者：
Iborra, Salvador;Martinez-Lopez, Maria;Cueto, Francisco J.;Conde-Garrosa, Ruth;Del Fresno, Carlos;Izquierdo, Helena M.;Abram, Clare L.;Mori, Daiki;Campos-Martin, Yolanda;Maria Reguera, Rosa;Kemp, Benjamin;Yamasaki, Sho;Robinson, Matthew J.;Soto, Manuel;Lowell, Clifford A.;Sancho, David
C型凝集素受体可感知多种内源性和外源性配体，这些配体可引发不同的反应。在这里，我们发现人类和小鼠Mincle与利什曼原虫释放的配体结合，利什曼原虫是一种逃避有效免疫反应的真核生物寄生虫。与野生型小鼠相比，Mincle缺陷型小鼠在利什曼原虫耳皮内感染后皮肤病理学较轻，寄生虫负荷仅为野生型小鼠的十分之一。Mincle缺陷增强了对寄生虫的适应性免疫，与Mincle缺陷树突状细胞（DC）的激活，迁移和引发增加相关。利什曼原虫触发Mincle依赖性抑制轴，其特征在于SHP 1与FcRγ链偶联。在CD 11c+细胞表型中SHP 1的选择性缺失增强了对利什曼原虫的适应性免疫。总之，利什曼原虫将Mincle转变为抑制性ITAM（伊塔米）构型，其损害DC活化。因此，伊塔米可以被病原体用于免疫逃避，并且可以代表感测自我和非自我的ITAM偶联受体的范例。
C-type lectin receptors sense a diversity of endogenous and exogenous ligands that may trigger differential responses. Here, we have found that human and mouse Mincle bind to a ligand released by Leishmania, a eukaryote parasite that evades an effective immune response. Mincle-deficient mice had milder dermal pathology and a tenth of the parasite burden compared to wild-type mice after Leishmania major intradermal ear infection. Mincle deficiency enhanced adaptive immunity against the parasite, correlating with increased activation, migration and priming by Mincle-deficient dendritic cells (DCs). Leishmania triggered a Mincle-dependent inhibitory axis characterized by SHP1 coupling to the FcRγ chain. Selective loss of SHP1 in CD11c+ cells phenocopies enhanced adaptive immunity to Leishmania. In conclusion, Leishmania shifts Mincle to an inhibitory ITAM (ITAMi) configuration that impairs DC activation. Thus, ITAMi can be exploited for immune evasion by a pathogen and may represent a paradigm for ITAM-coupled receptors sensing self and non-self.
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