美国布莱根妇女医院Francisco J. Quintana课题组开发出CD40⁺MHC-II⁺星形胶质细胞抗原呈递促进中枢神经系统自身免疫。相关论文发表在2026年8月5日出版的《自然》杂志上。

通过狂犬病条形码相互作用检测和测序，结合单细胞RNA测序、体外共培养系统和基于CRISPR–Cas9的细胞特异性体内遗传扰动研究，该团队证实了表达CD40和MHC-II的星形胶质细胞促进CNS T细胞自身免疫。小组通过SorTagging细胞间接触利用普遍标记免疫伙伴关系来分析星形胶质细胞相互作用的CD4⁺ T细胞，发现星形胶质细胞- CD4⁺ T细胞直接相互作用增强实验性自身免疫性脑脊髓炎的致病性T辅助17细胞反应。

此外，该团队还研究了这些相互作用对星形胶质细胞的影响。利用体内亚蛋白质组学方法和AlphaFold-Multimer预测，小组证实了CD4⁺ T细胞表达CD40L激活星形胶质细胞中的CD40诱导PLIN4阳性脂滴的积累，这些脂滴提供乙酰辅酶A，促进p65乙酰化依赖性NF-κB活化和抗原呈递。最后，该课题组研究人员通过单核RNA测序和免疫组织化学检测多发性硬化症样本中的CD40⁺MHC-II⁺LD⁺星形胶质细胞。总之，这些研究确定了星形胶质细胞促进中枢神经系统自身免疫的一种以前未被认识的机制。

据悉，星形胶质细胞参与多种神经系统疾病的病理，包括T细胞驱动的中枢神经系统自身免疫性疾病（CNS）多发性硬化症及其母细胞模型，实验性自身免疫性脑脊髓炎。然而，星形胶质细胞与CD4⁺ T细胞之间的功能相互作用知之甚少。

附：英文原文

Title: Antigen presentation by CD40+MHC-II+ astrocytes promotes CNS autoimmunity

Author: Lee, Joon-Hyuk, Li, Zhaorong, Soto, Joselyn S., Kim, Ah-Ram, Illouz, Tomer, Polonio, Carolina M., Kilian, Michael, Kenison, Jessica E., Schle, Anton M., Akl, Camilo Faust, Lee, Hong-Gyun, Andersen, Brian M., Ye, Jessica J., Rone, Joseph M., Piester, Gavin, Srun, Lena, Martinez, Jazmin, Danko, Austin, Lee, Jinsu, Heo, Tae Hyun, Chung, Elizabeth N., Oetjen, Landon K., Duart-Abadia, Pere, Koo, Nakyung, Perrimon, Norbert, Wheeler, Michael A., Khakh, Baljit S., Zandee, Stephanie E. J., Prat, Alexandre, Quintana, Francisco J.

Issue&Volume: 2026-08-05

Abstract: Astrocytes contribute to the pathology of multiple neurological disorders, including the T cell-driven autoimmune disease of the central nervous system (CNS) multiple sclerosis and its mouse model, experimental autoimmune encephalomyelitis1. However, little is known about functional interactions between astrocytes and CD4+ T cells. Here using rabies barcode interaction detection followed by sequencing2, in combination with single-cell RNA sequencing, in vitro co-culture systems and cell-specific in vivo CRISPR–Cas9-based genetic perturbation studies, we established that astrocytes expressing CD40 and MHC-II promote CNS T cell autoimmunity. We harnessed universal labelling immune partnerships by SorTagging intercellular contacts3 to analyse astrocyte-interacting CD4+ T cells, finding that direct astrocyte–CD4+ T cell interactions enhance pathogenic T helper 17 cell responses in experimental autoimmune encephalomyelitis. In addition, we studied the effect of these interactions on astrocytes. Using in vivo subproteomic approaches4 and AlphaFold-Multimer predictions5, we established that CD40 activation in astrocytes by CD40L expressed by CD4+ T cells induces the accumulation of PLIN4-positive lipid droplets, which provide acetyl-CoA to promote p65 acetylation-dependent NF-κB activation and antigen presentation. Finally, we detected CD40+MHC-II+LD+ astrocytes in multiple sclerosis samples by single-nucleus RNA sequencing and immunohistochemistry. In summary, these studies define a previously unrecognized mechanism by which astrocytes promote CNS autoimmunity.

DOI: 10.1038/s41586-026-10860-6

Source: https://www.nature.com/articles/s41586-026-10860-6