ALCAM on human oligodendrocytes mediates CD4 T cell adhesion.

Area of Science:

• Neuroimmunology
• Cellular and Molecular Neuroscience

Background:

• Multiple sclerosis (MS) is a chronic neuroinflammatory disease causing demyelination and neuroaxonal injury.
• Currently, no therapies exist to protect oligodendrocytes and their myelin sheaths from immune-mediated damage.
• Pro-inflammatory T helper 17 (Th17) cells directly injure oligodendrocytes in MS, but the underlying molecular mechanisms are unknown.

Purpose of the Study:

• To investigate the role of cell adhesion molecules (CAMs) on mature oligodendrocytes in interactions with Th17 cells.
• To identify potential therapeutic targets for neuroprotection in MS by understanding these detrimental interactions.

Main Methods:

• Single-cell RNA sequencing, flow cytometry, and immunofluorescence on human and murine CNS tissue.
• Analysis of human primary oligodendrocytes exposed to pro-inflammatory cytokines and activated T cells.
• In vitro live imaging, silencing, and blocking experiments targeting MCAM and ALCAM in Th17-oligodendrocyte interactions.

Main Results:

• Human and murine mature oligodendrocytes express melanoma cell adhesion molecule (MCAM) and activated leukocyte cell adhesion molecule (ALCAM).
• Inflammation and T cell contact downregulate MCAM but not ALCAM on human oligodendrocytes.
• Silencing or blocking ALCAM significantly reduced Th17 cell adhesion and cytotoxicity to human oligodendrocytes, protecting their processes.

Conclusions:

• Human oligodendrocytes express MCAM and ALCAM, with differential regulation by inflammation and T cell contact.
• ALCAM acts as a ligand for Th17 cells, mediating their adhesion and subsequent damage to oligodendrocytes.
• ALCAM represents a promising therapeutic target for neuroprotection in multiple sclerosis.