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

Area of Science:

• Neuroimmunology
• Cellular immunology
• Molecular neuroscience

Background:

• Astrocytes play a role in neurological disorders like multiple sclerosis (MS).
• Functional interactions between astrocytes and CD4+ T cells in the CNS are not well understood.
• Understanding these interactions is crucial for developing MS therapies.

Purpose of the Study:

• To investigate the functional interactions between astrocytes and CD4+ T cells in CNS autoimmunity.
• To identify mechanisms by which astrocytes promote T cell-mediated autoimmune responses in the CNS.
• To explore the role of astrocyte-CD4+ T cell interactions in experimental autoimmune encephalomyelitis (EAE) and MS.

Main Methods:

• Rabies barcode interaction detection followed by sequencing (RaBIDS).
• Single-cell RNA sequencing (scRNA-seq).
• In vitro co-culture systems and in vivo CRISPR-Cas9 genetic perturbation.
• SorTagging intercellular contacts.
• In vivo subproteomic approaches and AlphaFold-Multimer predictions.

Main Results:

• Astrocytes expressing CD40 and MHC-II were found to promote CNS T cell autoimmunity.
• Direct astrocyte-CD4+ T cell interactions enhance pathogenic T helper 17 cell responses in EAE.
• CD40 activation by CD4+ T cells induces lipid droplet accumulation in astrocytes, promoting NF-κB activation and antigen presentation.
• CD40+MHC-II+LD+ astrocytes were detected in human MS samples.

Conclusions:

• Astrocytes expressing CD40 and MHC-II are key drivers of CNS autoimmunity.
• A novel mechanism involving astrocyte lipid droplets, NF-κB activation, and antigen presentation in promoting autoimmunity is defined.
• These findings highlight a previously unrecognized role for astrocytes in promoting CNS autoimmune diseases like MS.