Brain-infiltrating CD4 T cells drive inflammatory microglia proliferation during cryptococcal meningitis in mice

作者：Sofia Hain, Man Shun Fu, L Wigg, L. George, David A.J. Lecky, Alexander J. Whitehead, Erin Clipston, Ko Sato, Masahiro Ono, Marcel Wüthrich, Bruce Klein, Kazuyoshi Kawakami, Julie Rayes, David Bending, Rebecca A. Drummond · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-64034-5 · 被引用次数：4 · 研究领域：Fungal Infections and Studies、Neuroinflammation and Neurodegeneration Mechanisms、Galectins and Cancer Biology

Cryptococcal meningitis is a fungal infection in patients with compromised CD4 T cell function. CD4 T cells provide killing signals to macrophages, principally IFNγ, to limit intracellular fungal replication. However, CD4 T cells may also drive inflammatory tissue damage. Yet, it is not fully understood how fungal-specific CD4 T cells infiltrate the brain and how they influence functional phenotypes of CNS-resident myeloid cells. In the current work, we develop a mouse model to track fungal-specific CD4 T cells and determine their influence on microglia. We found IFNγ+ fungal-specific CD4 T cells have limited TCR signalling and characterise a population of inflammatory microglia that upregulate MHCII and IFNγ-regulated genes during infection. Inflammatory microglia have poor fungicidal capacity and significantly expand during infection, a process that depends on CD4 T cell infiltration. Taken together, these data identify the early inflammatory consequences of fungal-specific CD4 T cell infiltration and identify proliferating microglia as important drivers of brain inflammation during infection.