A molecular switch in mouse CD1d modulates natural killer T cell activation by α-galactosylsphingamides.
A molecular switch in mouse CD1d modulates natural killer T cell activation by α-galactosylsphingamides.
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小鼠 CD1d 中的分子开关通过 α-半乳糖基鞘氨酰胺调节自然杀伤 T 细胞的激活。
DOI：
10.1074/jbc.ra119.009963
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Zajonc,DirkM
中科院分区：
文献类型：
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作者：
Wang,Jing;Guillaume,Joren;Janssens,Jonas;Remesh,SoumyaG;Ying,Ge;Bitra,Aruna;VanCalenbergh,Serge;Zajonc,DirkM
I型自然杀伤T细胞是一群先天的类T淋巴细胞，通过产生促炎和抗炎细胞因子，对α-GalCer产生快速反应。在开发新的α-GalCer类似物时，由于它们产生促炎细胞因子(Th1型刺激物)，因此被用作潜在的佐剂，我们产生了α-半乳糖鞘氨酰胺(αGSA)。令人惊讶的是，αGSA并不是有效的抗活体蛋白，尽管它们与T细胞受体(TcR)有很强的亲和力。在这里，我们使用表面等离子共振、抗原呈递分析和X射线结晶学(得到19个不同的二元(CD1d-糖脂)或三元(CD1d-糖脂-Tcr)化合物的晶体结构，分辨率在1.67到2.85ó之间)，表征了小鼠NKT细胞识别αGSA的生化和结构细节。我们在小鼠(M)CD1d中发现了一个分子开关，它通过αGSA调节NKT细胞的激活。我们发现分子开关涉及mCD1d的Tyr-73与αGSA的酰胺基氧之间的氢键相互作用。我们进一步证实，酰链的长度控制着酰胺基团相对于分子开关的位置，并与Tyr-73协同作用来控制NKT细胞的活性。总而言之，我们的发现揭示了在非极性环境中呈现和识别带有极性部分的糖脂的重要机制。这些观察结果可能为开发αGSA作为特异性NKT细胞拮抗剂来调节免疫反应提供信息。
Type I natural killer T (NKT) cells are a population of innate like T lymphocytes that rapidly respond to α-GalCer presented by CD1d via the production of both pro- and anti-inflammatory cytokines. While developing novel α-GalCer analogs that were meant to be utilized as potential adjuvants because of their production of pro-inflammatory cytokines (Th1 skewers), we generated α-galactosylsphingamides (αGSA). Surprisingly, αGSAs are not potent antigensin vivodespite their strong T-cell receptor (TCR)–binding affinities. Here, using surface plasmon resonance (SPR), antigen presentation assays, and X-ray crystallography (yielding crystal structures of 19 different binary (CD1d-glycolipid) or ternary (CD1d-glycolipid-TCR) complexes at resolutions between 1.67 and 2.85 Å), we characterized the biochemical and structural details of αGSA recognition by murine NKT cells. We identified a molecular switch within murine (m)CD1d that modulates NKT cell activation by αGSAs. We found that the molecular switch involves a hydrogen bond interaction between Tyr-73 of mCD1d and the amide group oxygen of αGSAs. We further established that the length of the acyl chain controls the positioning of the amide group with respect to the molecular switch and works synergistically with Tyr-73 to control NKT cell activity. In conclusion, our findings reveal important mechanistic insights into the presentation and recognition of glycolipids with polar moieties in an otherwise apolar milieu. These observations may inform the development αGSAs as specific NKT cell antagonists to modulate immune responses.