TMEM119+ microglia MHC class I restricted antigen presentation impacts CD8 T cell memory, effector status, and...

Area of Science:

• Neuroimmunology
• Virology
• Immunology

Background:

• Microglia, the immune cells of the central nervous system (CNS), play a critical role in neuroinflammation.
• The precise mechanisms by which microglia present antigens to CD8 T cells during viral infections are not fully understood.
• Understanding these interactions is crucial for developing therapies for viral encephalitis and other neurological disorders.

Purpose of the Study:

• To investigate the distinct roles of microglial MHC class I molecules (H-2K^b and H-2D^b) in regulating CD8 T cell responses during Theiler's murine encephalomyelitis virus (TMEV) infection.
• To elucidate how these microglial antigen presentation pathways influence T cell proliferation, effector functions, memory formation, and neuropathology.

Main Methods:

• Generation of Tmem119 conditional knockout mice lacking specific MHC class I molecules on microglia.
• Infection of these mice with TMEV to model neurotropic viral infection.
• Analysis of CD8 T cell responses, including proliferation, perforin levels, tissue-resident memory cell reactivation, and blood-brain barrier integrity.

Main Results:

• Microglial H-2K^b was found to promote antiviral CD8 T cell proliferation in the brain.
• Microglial H-2D^b enhanced CD8 T cell perforin levels and contributed to blood-brain barrier (BBB) disruption.
• Microglial H-2D^b was critical for the reactivation of CD8 tissue-resident memory T cells and subsequent BBB disruption, even after viral clearance.

Conclusions:

• Individual MHC class I genes on microglia have distinct functions in orchestrating CD8 T cell-mediated immunity during viral CNS infections.
• Microglial H-2K^b and H-2D^b differentially regulate CD8 T cell proliferation, effector functions, and memory recall.
• These findings highlight specific microglial pathways involved in neuropathology and suggest potential therapeutic targets for viral-induced neurological damage.