T cell-microglial interactions that impair myelin maintenance and regeneration: cellular mechanisms on white-matter associated changes.

White matter changes are a hallmark of aging and neurodegenerative diseases, characterized by progressive myelin deterioration and impaired regenerative capacities. Growing evidence indicates that maladaptive interactions between microglia and infiltrating T lymphocytes contribute to the progression of white matter changes. Recent single-cell and spatial transcriptomic studies have revealed aging-associated shifts in microglial and T cell states, offering new insights into how aging reshapes the immune-glial landscape. This review summarizes the cellular and molecular evidence across species, with emphasis on murine models, showing that aging alters microglial signaling profiles and promotes the recruitment of CD8⁺ T cells through cytokine signaling. We further examined how T cell-derived interferon-gamma induces transcriptional changes in microglia and oligodendrocyte lineage cells. The resulting interferon-responsive glial states destabilize myelin and limit remyelination, which are characteristic features of aging, multiple sclerosis, and neurodegeneration. By integrating molecular, genetic, and cellular insights, this review proposes a mechanistic framework using recent studies for how T cell-microglial interactions contribute to white matter alterations in aging and highlights the therapeutic opportunities to restore homeostasis and promote remyelination.