CD40 ligand and IFN-γ induce proinflammatory activity and microglia-mediated neurodegeneration in human stem cell models

CD40L plus IFN-γ drives robust inflammatory cytokine release and cell death in hiPSC-derived microglia, and CD40L blockade reverses both outcomes.

• Why it matters: The CD40/T cell CD40L interaction is linked to MS neuroinflammation, but its functional consequences in human brain-like models remain unclear.
• What they did: Human iPSC-derived microglia were stimulated with CD40L and IFN-γ, with anti-CD40L antibody used to test effects on cell death, inflammatory output, and transcriptional changes.
• The result: In an hiPSC neuron–astrocyte–microglia tri-culture, CD40L plus IFN-γ caused microglia-dependent neuronal dysregulation and death, and anti-CD40L substantially attenuated neuronal injury.

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