Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin
Control of CD1d-restricted antigen presentation and inflammation by sphingomyelin
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DOI：
10.1038/s41590-019-0504-0
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发表时间：
2019-12-01
影响因子：
30.5
通讯作者：
Blumberg, Richard S.
中科院分区：
文献类型：
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作者：
Melum, Espen;Jiang, Xiaojun;Blumberg, Richard S.
不变的自然杀伤T（iNKT）细胞识别由CD 1d呈递的激活自身和微生物脂质。CD 1d也可以结合非活化脂质，如鞘磷脂。我们假设，这些作为内源性调节剂，并调查人类和小鼠缺乏酸性鞘磷脂酶（ASM），一种酶，降解鞘磷脂。我们发现，小鼠中ASM的缺失导致胸腺中CD 1d限制性抗原呈递和iNKT细胞选择减少，导致iNKT细胞水平降低和对iNKT细胞介导的炎症性疾病的抵抗。在患有尼曼-皮克病的ASM缺陷型人体中也观察到抗原提呈缺陷和iNKT细胞减少，而健康人体中的ASM活性与iNKT细胞表型相关。药理学ASM给药促进抗原呈递并恢复ASM缺陷小鼠中iNKT细胞的水平。总之，这些结果表明，非激动性CD 1d相关脂质的控制对于iNKT细胞在体内的发育和功能至关重要，并且代表了细胞鞘脂代谢和免疫之间的紧密联系。
Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann-Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.