Brain-infiltrating CD4 T cells drive inflammatory microglia proliferation during cryptococcal meningitis in mice
- Sofia Hain
- Man Shun Fu
- Lucy Wigg
- Lorna George
- David Lecky
- Alexander J. Whitehead
- Erin Clipston
- Ko Sato
- Masahiro Ono
- Marcel Wuthrich
- Bruce Klein
- Kazuyoshi Kawakami
- Julie Rayes
- David Bending
- Rebecca A. Drummond
2025-10-09
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.