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Brain-infiltrating CD4 T cells drive inflammatory microglia proliferation during cryptococcal meningitis in mice
Sofia Hain1, Man Shun Fu1, Lucy Wigg2
1Institute of Immunology & Immunotherapy, University of Birmingham, Birmingham, UK.
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.
Insights
Fungal meningitis involves CD4 T cells that can harm the brain. This study shows these T cells promote inflammatory microglia, worsening brain inflammation and fungal infection.
Area of Science:
- Neuroimmunology
- Infectious Diseases
- Microbiology
Background:
- Cryptococcal meningitis is a serious fungal infection affecting patients with weakened CD4 T cell immunity.
- CD4 T cells are crucial for controlling fungal infections but can also cause damaging inflammation in the central nervous system (CNS).
- The precise mechanisms of CD4 T cell infiltration into the brain and their impact on CNS-resident myeloid cells during fungal meningitis remain unclear.
Purpose of the Study:
- To investigate the infiltration dynamics of fungal-specific CD4 T cells into the brain.
- To elucidate the functional impact of these CD4 T cells on microglia phenotypes during infection.
- To understand the role of microglia proliferation in driving brain inflammation during cryptococcal meningitis.
Main Methods:
- Development of a mouse model to track fungal-specific CD4 T cells.
- Analysis of CD4 T cell signaling and microglial gene expression (MHCII, IFNγ-regulated genes).
- Assessment of microglial fungicidal capacity and proliferation during infection.
Main Results:
- Fungal-specific CD4 T cells exhibited limited T cell receptor (TCR) signaling upon brain infiltration.
- A distinct population of inflammatory microglia was identified, characterized by upregulated MHCII and IFNγ-regulated genes.
- These inflammatory microglia demonstrated reduced fungicidal activity and significant proliferation, dependent on CD4 T cell infiltration.
Conclusions:
- Fungal-specific CD4 T cell infiltration into the CNS triggers early inflammatory responses.
- Proliferating inflammatory microglia are key contributors to brain inflammation during fungal meningitis.
- Targeting microglial activation may offer therapeutic strategies for cryptococcal meningitis.
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