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Publications

Journal Article Ahead of print 2 citations

PubMed: 42557325 DOI: 10.1038/s41586-026-10860-6

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

Nature

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

Affiliations

  • Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Department of Physiology, University of California, Los Angeles, CA, USA.
  • Department of Genetics, Harvard Medical School, Boston, MA, USA.
  • Department of Neurology, Veterans Affairs Medical Center, Harvard Medical School, Boston, MA, USA.
  • Howard Hughes Medical Institute, Boston, MA, USA.
  • Department of Neurobiology, University of California, Los Angeles, CA, USA.
  • Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
  • Neuroimmunology Research Lab, CRCHUM and Department of Neuroscience, Faculty of Medicine, Universite de Montreal, Montreal, Quebec, Canada.
  • Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • The Broad Institute of Harvard and MIT, Cambridge, MA, USA.

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 encephalomyelitis 1. However, little is known about functional interactions between astrocytes and CD4 + T cells. Here using rabies barcode interaction detection followed by sequencing 2, 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 contacts 3 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 approaches 4 and AlphaFold-Multimer predictions 5, 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.

MeSH

Cells, Sclerosis, Multiple Sclerosis, Astrocytes, Encephalomyelitis, Antigen Presentation, Encephalomyelitis, Autoimmune, Experimental, Autoimmunity