Pathogenic Microglia Orchestrate Neurotoxic Properties of Eomes-Expressing Helper T Cells.

Area of Science:

• Neuroimmunology
• Neuroinflammation
• Microglia biology

Background:

• Microglia, the immune cells of the central nervous system (CNS), are implicated in neurodegeneration.
• Specific microglial subsets with MHC-II and IFN-I signatures may play pathogenic roles, but their significance is unclear.
• These subsets could contribute to neuroinflammation in conditions like multiple sclerosis (MS).

Purpose of the Study:

• To investigate the role of MHC-II and IFN-I expressing microglial subsets in neurodegeneration.
• To elucidate the mechanisms by which these microglia subsets interact with T cells.
• To explore the therapeutic potential of targeting these pathways in neurodegenerative diseases.

Main Methods:

• Utilized experimental autoimmune encephalomyelitis (EAE) model, a model for MS.
• Analyzed microglial activation states, including IFN-I and MHC-II signatures.
• Investigated the interaction between microglia and Eomes+ T cells.
• Assessed the effect of a long interspersed nuclear element-1 (L1) inhibitor on EAE progression.

Main Results:

• Identified specific microglial subsets with MHC-II and IFN-I signatures in the neurodegenerative phase of EAE.
• Demonstrated that microglia acquire IFN-I signatures upon sensing ectopic L1 gene expression.
• Showed that L1-encoded ORF1 protein stimulates Eomes+ T cells via microglia-MHC-II presentation.
• Found that L1 inhibitor treatment ameliorated EAE symptoms and reduced CNS T cell infiltration.

Conclusions:

• New microglial subsets with MHC-II and IFN-I signatures act as a neuroinflammatory hub in immune-mediated neurodegeneration.
• L1 expression and its encoded proteins contribute to neuroinflammation by modulating microglial and T cell responses.
• Targeting L1 may offer a therapeutic strategy for neurodegenerative diseases like MS.