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

Astrocytes adapt to injury and disease by entering reactive states with altered gene expression, morphology, and function, but we know little about how these states evolve over time in the human setting. Using human cortical organoids and primary fetal cortical tissue, we mapped the temporal dynamics of inflammatory astrocytes. Brief and prolonged exposure to inflammatory cytokines elicited distinct time-dependent transcriptomic and chromatin accessibility signatures. Astrocytes that experienced either acute or chronic cytokine exposure reverted to a quiescent genomic state within days of cytokine withdrawal. Unexpectedly, only chronic inflammation revealed induction of major histocompatibility complex class II (MHC class II) expression in astrocytes. We validated MHC class II expression and surface localization in organotypic fetal cortical slices and human pathological sections. We also found evidence that delayed MHC class II emergence reflects progressive activation of interferon-linked signaling in astrocytes. Through co-immunoprecipitation of MHC class II complexes from cytokine-treated astrocytes, we demonstrate the presence of MHC class II-presented peptides, which include neuronal debris.