Context-dependent effects of adaptive immunity on IFN-α–mediated neurotoxicity in Aicardi–Goutières syndrome

Aicardi–Goutières syndrome (AGS) is a severe neuroinflammatory disorder characterized by chronic overexpression of interferon-alpha (IFN-α) in the central nervous system (CNS), leading to progressive encephalopathy, developmental regression, and high mortality. Recent work has identified the brain microvasculature, particularly the blood-brain barrier (BBB) endothelial cells, as a central mediator of IFN-α–induced neurotoxicity. This microangiopathy is accompanied by the infiltration of B and T lymphocytes into the brain parenchyma, but their contribution to disease progression remains unclear. Here, we investigated the role of adaptive immune cells in AGS pathogenesis using a transgenic mouse model that overexpresses IFN-α in the brain, but lacks mature B and T cells. Loss of adaptive immune cells partially ameliorated IFN-α–driven neurotoxicity, improving neurological disease and reducing histopathological damage, without altering interferon or interferon-stimulated gene expression. These findings indicate that adaptive immunity is not essential but modulates specific aspects of disease. Together, our results support a model in which IFN-α primarily targets CNS-resident cells, such as endothelial cells, astrocytes, and microglia, while adaptive immune responses act as a secondary enhancer of pathology. This work provides new mechanistic insight into AGS and highlights therapeutic opportunities aimed at modulating IFN-α signalling or glial-driven neuroinflammation to slow disease progression. • Loss of adaptive immunity partially rescues IFN-α–induced neurological disease. • Absence of T and B cells abolishes brain calcifications in IFN-α mice. • Lymphocytes amplify IFN-α-driven neuroinflammation and tissue degeneration. • CNS-resident ISG expression persists despite lymphocyte depletion. • Microglia counteract lymphocyte-driven injury, revealing opposing immune roles.