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Antigen presentation by CD40+MHC-II+ astrocytes promotes CNS autoimmunity
Nature
(2026) Cite this article
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.
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The analysis results and bioinformatics data have been deposited into the Zenodo61 repository 19803100 (https://zenodo.org/records/19803100). scRNA-seq or single-nucleus RNA-seq datasets of astrocytes were obtained from the Gene Expression Omnibus with accession numbers GSE150858 (ref. 2), GSE130119 (ref. 8), GSE180759 (ref. 29) and the BioProject repository PRJNA544731 (ref. 30). All other data are available from the corresponding author on reasonable request. Correspondence and request for materials should be addressed to F.J.Q. Source data are provided with this paper.
Lee, H. G., Lee, J. H., Flausino, L. E. & Quintana, F. J. Neuroinflammation: an astrocyte perspective. Sci. Transl. Med. 15, eadi7828 (2023).
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