Lysosomal processing of sulfatide analogs alters target NKT cell specificity and immune responses in cancer.
Lysosomal processing of sulfatide analogs alters target NKT cell specificity and immune responses in cancer.
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硫苷脂类似物的溶酶体加工改变了癌症中的靶 NKT 细胞特异性和免疫反应。
DOI：
10.1172/jci165281
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
How
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作者：
Nishio,Kumiko;Pasquet,Lise;Camara,Kaddy;DiSapio,Julia;Hsu,KevinS;Kato,Shingo;Bloom,Anja;Richardson,StewartK;Welsh,JoshuaA;Jiang,Tianbo;Jones,JenniferC;Cardell,Susanna;Watarai,Hiroshi;Terabe,Masaki;Olkhanud,PurevdorjB;How
在一项典型刺激II型NKT细胞的硫脂结构-功能研究中，我们有了一个意想不到的发现。我们比较了与鞘氨醇或植鞘氨醇以及具有0-1-2双键(C或pC24：0、24：1或24：2)的24碳酰链的类似物。CD1d单体在塑料刺激的II型NKT细胞杂交瘤中呈现C24：1和C24：2硫代产物，而不是I型NKT细胞杂交瘤。出乎意料的是，当由骨髓来源的DC(BMDCs)呈现时，C24：2逆转了特异性，刺激I型而不是II型NKT细胞杂交瘤，模拟相应的β-半乳糖神经酰胺(βGalCer)而不是硫酸盐。C24：2诱导干扰素-γ依赖的免疫保护作用对抗CT26结肠癌肺转移，扭曲细胞因子谱，激活常规DC亚群1细胞(CDC1s)。这可以通过用巴菲尔霉素A1阻断溶酶体加工，或通过亚硫酸盐阻断芳基硫酸酯酶或删除这种分解硫酸盐的酶来消除。因此，C24：2在BMDCs中被意外地从II型NKT细胞刺激配体处理为I型NKT细胞刺激配体，促进了肿瘤免疫。我们认为这是首次发现糖基神经酰胺的抗原处理改变了靶细胞的特异性，逆转了糖脂的功能，从刺激II型NKT细胞到刺激I型NKT细胞，从而在癌症中引入了保护性功能活性。我们还相信，我们的研究揭示了抗原处理的新角色，它不涉及MHC负载，而是改变哪种类型的细胞做出反应。
In a structure-function study of sulfatides that typically stimulate type II NKT cells, we made an unexpected discovery. We compared analogs with sphingosine or phytosphingosine chains and 24-carbon acyl chains with 0-1-2 double bonds (C or pC24:0, 24:1, or 24:2). C24:1 and C24:2 sulfatide presented by the CD1d monomer on plastic stimulated type II, not type I, NKT cell hybridomas, as expected. Unexpectedly, when presented by bone marrow–derived DCs (BMDCs), C24:2 reversed specificity to stimulate type I, not type II, NKT cell hybridomas, mimicking the corresponding β-galactosylceramide (βGalCer) without sulfate. C24:2 induced IFN-γ–dependent immunoprotection against CT26 colon cancer lung metastases, skewed the cytokine profile, and activated conventional DC subset 1 cells (cDC1s). This was abrogated by blocking lysosomal processing with bafilomycin A1, or by sulfite blocking of arylsulfatase or deletion of this enyzme that cleaves off sulfate. Thus, C24:2 was unexpectedly processed in BMDCs from a type II to a type I NKT cell–stimulating ligand, promoting tumor immunity. We believe this is the first discovery showing that antigen processing of glycosylceramides alters the specificity for the target cell, reversing the glycolipid’s function from stimulating type II NKT cells to stimulating type I NKT cells, thereby introducing protective functional activity in cancer. We also believe our study uncovers a new role for antigen processing that does not involve MHC loading but rather alteration of which type of cell is responding.