近日，美国国立卫生研究院教授John J. O’Shea及其团队研制了鞘糖脂合成对自然杀伤和细胞毒性T细胞的选择性要求。2025年4月29日，国际知名学术期刊《细胞》发表了这一成果。

表现出复杂调控的细胞身份基因被超级增强子（SE）结构标记。在自然杀伤细胞（NK）的SEs评估鉴定Ugcg，编码的酶负责鞘糖脂（GSL）合成。在早期造血过程中，条件删除Ugcg会破坏NK细胞的生成，而保留其他谱系。药理抑制UGCG破坏细胞毒性颗粒和细胞毒性，减少病毒感染后的扩张，促进细胞凋亡。B4galt5转录UGCG下游的一种酶，具有SE结构。添加其产物乳糖神经酰胺（LacCer），可逆转UGCG抑制引起的细胞凋亡。相比之下，复杂的GSLs，如asialo-GM1，不需要NK细胞活力和颗粒完整性。在病毒感染期间，Ugcg和B4galt5在CD8⁺ T细胞中上调，与细胞毒性机制的获得相关。缺乏Ugcg的抗原特异性CD8⁺ T细胞在感染期间不能扩增。他们的研究揭示了GSL代谢在NK和CD8⁺ T细胞生物学中的选择性和必要作用。

附：英文原文

Title: Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells

Author: Tasha A. Morrison, Jaelyn Vigee, Kevin A. Tovar, Taylor A. Talley, Adriana M. Mujal, Mari Kono, Rachael Philips, Hiroyuki Nagashima, Stephen R. Brooks, Hannah Dada, Isaiah Rozich, Kelly Hudspeth, Colleen M. Lau, Chen Yao, Giuseppe Sciumè, Hong-Wei Sun, Juan S. Bonifacino, Yuka Kanno, Michael L. Dustin, Davide Randazzo, Richard L. Proia, Joseph C. Sun, Han-Yu Shih, John J. O’Shea

Issue&Volume: 2025-04-29

Abstract: Cell identity genes that exhibit complex regulation are marked by super-enhancer (SE) architecture. Assessment of SEs in natural killer (NK) cells identified Ugcg, encoding the enzyme responsible for glycosphingolipid (GSL) synthesis. Conditional deletion of Ugcg in early hematopoiesis abrogated NK cell generation while sparing other lineages. Pharmacological inhibition of UGCG disrupted cytotoxic granules and cytotoxicity, reduced expansion after viral infection, and promoted apoptosis. B4galt5 transcribes an enzyme downstream of UGCG and possesses SE structure. Addition of its product, lactosylceramide (LacCer), reversed apoptosis due to UGCG inhibition. By contrast, complex GSLs, such as asialo-GM1, were not required for NK cell viability and granule integrity. Ugcg and B4galt5 were upregulated in CD8+ T cells during viral infection, correlating with the acquisition of cytotoxic machinery. Antigen-specific CD8+ T cells lacking Ugcg failed to expand during infection. Our study reveals a selective and essential role of GSL metabolism in NK and CD8+ T cell biology.

DOI: 10.1016/j.cell.2025.04.007

Source: https://www.cell.com/cell/abstract/S0092-8674(25)00409-X