T cells promote microglia-mediated synaptic elimination and cognitive dysfunction during recovery from...

Area of Science:

• Neuroscience
• Immunology
• Virology

Background:

• T cells are crucial for clearing viral infections in the central nervous system (CNS).
• T cells dynamically regulate brain functions, including spatial learning, via cytokine signaling.
• The long-term impact of persistent T cells after neurotropic flavivirus recovery on cognitive function remains unclear.

Purpose of the Study:

• To investigate whether persistent hippocampal T cells after West Nile virus (WNV) or Zika virus (ZIKV) infection affect hippocampal-dependent learning and memory.
• To elucidate the mechanisms by which T cells mediate post-infectious cognitive deficits.

Main Methods:

• Utilized newly established models of viral encephalitis recovery in adult mice.
• Assessed spatial learning and memory deficits in recovered WNV and ZIKV infected mice.
• Investigated the role of T cell-derived interferon-gamma (IFN-γ) signaling in microglia using genetic deficiency models (CD8+ T cell deficient, IFN-γ signaling deficient microglia).

Main Results:

• Mice recovered from WNV or ZIKV infection exhibited spatial learning impairments.
• T cell-derived IFN-γ signaling in microglia was identified as a key mediator of these deficits.
• WNV infection recovery led to presynaptic terminal elimination without repair, while ZIKV recovery caused neuronal apoptosis and postsynaptic terminal loss.
• Mice deficient in CD8+ T cells or microglial IFN-γ signaling were protected against WNV-induced synapse elimination and showed improved synapse recovery after ZIKV infection.

Conclusions:

• T cell signaling to microglia drives cognitive impairments following neurotropic flavivirus infections.
• These findings highlight virus-specific mechanisms underlying post-infectious cognitive sequelae.
• Targeting T cell-microglia communication may offer therapeutic strategies for neurocognitive deficits after viral encephalitis.