Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation

Astrocytes adapt to injury and disease by entering a reactive state defined by transcriptomic, morphological, and functional changes. Using a combination of human cortical organoids (hCOs) and primary fetal brain tissue, we investigated the plasticity of human astrocyte reactivity. We observed robust inflammatory transcriptomic and chromatin signatures following cytokine exposure, which varied with duration. To assess reversibility, we withdrew cytokines after acute or chronic exposure. In both cases, astrocytes returned to a quiescent genomic state within days. Chronic exposure induced MHC class II gene expression, normally restricted to professional antigen-presenting cells. We validated MHCII protein in primary tissue and hCOs and used co-immunoprecipitation and mass spectrometry to identify candidate antigens. Finally, we showed that exogenous peptides from fetal neurons could be presented by astrocytic MHCII.