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 and Rebecca A. Drummond ()
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Sofia Hain: University of Birmingham
Man Shun Fu: University of Birmingham
Lucy Wigg: University of Birmingham
Lorna George: University of Birmingham
David Lecky: University of Birmingham
Alexander J. Whitehead: University of Wisconsin-Madison
Erin Clipston: University of Birmingham
Ko Sato: Tohoku University Graduate School of Medicine
Masahiro Ono: Imperial College London
Marcel Wuthrich: University of Wisconsin-Madison
Bruce Klein: University of Wisconsin-Madison
Kazuyoshi Kawakami: Tohoku University Graduate School of Medicine
Julie Rayes: University of Birmingham
David Bending: University of Birmingham
Rebecca A. Drummond: University of Birmingham

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-64034-5

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