埃默里大学医学院Rafi Ahmed小组近日取得一项新成果。经过不懈努力，他们的最新研究提出了暴露的磷脂酰丝氨酸是T细胞衰竭的抑制分子。2026年3月25日出版的《自然》发表了这项成果。

在这里，该团队评估了表面脂质代谢物磷脂酰丝氨酸（PS）作为衰竭的调节剂。PS主要定位于活细胞的内质膜，但众所周知，在细胞死亡期间，它会外化到外膜。暴露的PS对活免疫细胞的作用尚不清楚。该课题组发现活的抗原特异性CD8 T细胞在淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染期间外化PS。T细胞激活诱导初始PS暴露，慢性抗原刺激抑制外化。转录组学和脂质组学分析也发现PS在衰竭的CD8 T细胞中积累。

为了评估暴露的PS在衰竭中的作用，课题组研究人员用PS靶向抗体（mch1N11）4治疗LCMV慢性感染小鼠，发现它扩大了LCMV特异性CD8反应。PD1⁺TCF1⁺干细胞样CD8 T细胞在抗体处理后下调静止相关基因模块并增加增殖，突出了PS的抑制作用。从机制上讲，暴露在T细胞上的PS从外部抑制树突状细胞的免疫刺激表型，从而限制CD8 T细胞的反应。PS靶向抗体与抗PDL1协同增加CD8应答，改善病毒控制。最后，研究团队发现来自人类肿瘤的PD1⁺ CD8 T细胞也可以暴露PS。总之，该课题组人员详细介绍了CD8 T细胞PS生物学，并深入了解了暴露的PS作为“非经典”外源性抑制分子在呼气中的作用机制。

研究人员表示，在癌症和慢性感染中，CD8 T细胞的衰竭以抑制受体如PD1、TIM3、LAG3等的表达为特征。因此，抑制分子聚焦仅限于细胞表面蛋白。

附：英文原文

Title: Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion

Author: Medina, Christopher B., Sobierajska, Ewelina, Gong, Minghao, McManus, Daniel T., Thapa, Maheshwor, Lee, Judong, Im, Se Jin, Toombs, Jason E., Mitchell, Joshua M., Wang, Yating, Carlisle, Jennifer W., Freeman, Gordon J., Master, Viraj A., Ramalingam, Suresh S., Kissick, Haydn T., Li, Shuzhao, Brekken, Rolf A., Ahmed, Rafi

Issue&Volume: 2026-03-25

Abstract: In cancer and chronic infection, CD8 T cell exhaustion is hallmarked by expression of inhibitory receptors such as PD1, TIM3, LAG3 and others1,2,3. Thus, inhibitory molecule focus has been limited to cell-surface proteins. Here we evaluate the surface lipid metabolite phosphatidylserine (PS) as a regulator of exhaustion. PS primarily localizes to the inner plasma membrane of live cells but is well known to be externalized to the outer membrane during cell death. The role of exposed PS on live immune cells is less clear. We show that viable, antigen-specific CD8 T cells externalize PS during lymphocytic choriomeningitis virus (LCMV) infection. T cell activation induced initial PS exposure, and chronic antigen stimulation sustained externalization. Transcriptomic and lipidomic analyses also identified PS accumulation in exhausted CD8 T cells. To evaluate a role for exposed PS in exhaustion, we treated LCMV chronically infected mice with a PS-targeting antibody (mch1N11)4 and found that it expanded LCMV-specific CD8 responses. PD1+TCF1+ stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after antibody treatment, highlighting an inhibitory role for PS. Mechanistically, exposed PS on T cells functioned extrinsically to suppress dendritic cell immunostimulatory phenotypes, in turn limiting CD8 T cell responses. PS-targeting antibody with anti-PDL1 synergized to increase CD8 responses and improve viral control. Finally, we show that PD1+ CD8 T cells from human tumours can also expose PS. In summary, we detail CD8 T cell PS biology and provide insight into a mechanism by which exposed PS functions as a ‘non-classical’ extrinsic inhibitory molecule in exhaustion.

DOI: 10.1038/s41586-026-10266-4

Source: https://www.nature.com/articles/s41586-026-10266-4