Central nervous system microglial cell activation and proliferation follows direct interaction with...

Central nervous system (CNS)-resident macrophages (microglia) normally express negligible or low level MHC class II, but this is up-regulated in graft-vs-host disease (GvHD), in which a sparse CNS T cell infiltrate is observed. Relative to microglia from the normal CNS, those from the GvHD-affected CNS exhibited a 5-fold up-regulation of characteristically low CD45, MHC class II expression was increased 10- to 20-fold, and microglial cell recoveries were enhanced substantially. Immunohistologic analysis revealed CD4+ alphabetaTCR+CD2+ T cells scattered infrequently throughout the CNS parenchyme, 90% of which were blast cells of donor origin. An unusual clustering of activated microglia expressing strongly enhanced levels of CD11b/c and MHC class II was a feature of the GvHD-affected CNS, and despite the paucity of T lymphocytes present, activated microglial cell clusters were invariably intimately associated with these T cells. Moreover, 70% of T cells in the CNS were associated with single or clustered MHC class II+ microglia, and interacting cells were predominantly deep within the tissue parenchyme. Approximately 3.7% of the microglia that were freshly isolated from the GvHD-affected CNS were cycling, and proliferating cell nuclear Ag-positive microglia were detected in situ. Microglia from GvHD-affected animals sorted to purity by flow cytometry and cultured, extended long complex processes, exhibited spineous processes, and were phagocytic and highly motile. These outcomes are consistent with direct tissue macrophage-T cell interactions in situ that lead to activation, proliferation, and expansion of the responding tissue-resident cell.