Temporal regulation of human reactive astrocytes reveals their capacity for antigen presentation
Publication date: 30/03/2026
Authors: Emily Jane Hill, Caitlin Sojka, Maureen McGuirk Sampson et al.
Journal: Neuron
Commentary: In response to injury and disease, astrocytes exhibit reactive states characterised by alterations in gene expression, morphology, and function. On the other hand, it is unclear how these states develop over time in a human context. In this study, Hill et al. investigated the temporal dynamics of astrocyte inflammation using human cortical organoids (hCOs) and primary fetal cortical tissue. First the authors used a cytokine cocktail (TNF-α, IL-1α, and C1q) to induce a canonical inflammatory state in hCO-derived astrocytes. RNA-seq confirmed the upregulation of classic reactive markers like C3 and IL-6, aligning with established literature. The TIC was administered to hCO for one to three months. Through RNA-seq and ATAC-seq analyses, the authors identified three distinct genomic modules: a suppressed module composed by genes and regulatory regions whose expression is downregulated across all time points. Time-Independent module characterised by genes and accessible regions activated within 24 hours and maintained over time. Time-dependent module identified by genes and regions induced gradually over weeks or months. Notably, this module includes genes essential for antigen presentation via MHC class II. Astrocytes under chronic inflammatory conditions exhibited surface expression of MHC II, association with the invariant chain CD74, and the functional capability to process and present neuronal peptides, as confirmed by co-immunoprecipitation and mass spectrometry. These findings were further validated in organotypic human fetal brain sections and pathological adult brain samples, such as bacterial abscesses and aged tissues. Surprisingly, both acute and chronic reactive states were found to be reversible. Indeed, when cytokines are removed, astrocytes re-establish a quiescent state. This study demonstrates that human astrocytes under chronic inflammation activate reversible genomic programmes and acquire a previously unrecognised ability to present antigens via the MHC class II complex, providing a new mechanistic basis for understanding their active role in neurological diseases and potential therapies.
Commented by: Michele Tufano
DOI: https://doi.org/10.1016/j.neuron.2026.02.025
