CENTRAL-NERVOUS-SYSTEM MICROGLIAL CELL ACTIVATION AND PROLIFERATION FOLLOWS DIRECT INTERACTION WITH TISSUE-INFILTRATING T-CELL BLASTS

Central nervous system (CNS)-resident macrophages (microglia) normally express negligible or low level MHC class II, but this is up-regulate d in graft-vs-host disease (GvHD), in which a sparse CNS T cell infilt rate is observed. Relative to microglia from the normal CNS, those fro m the GvHD-affected CNS exhibited a 5-fold up-regulation of characteri stically low CD45, MMC class Ii expression was increased 10- to 20-fol d, and microglial cell recoveries were enhanced substantially. Immunoh istologic analysis revealed CD4(+)alpha beta TCR(+)CD2(+) T cells scat tered infrequently throughout the CNS parenchyme, 90% of which were bl ast cells of donor origin. An unusual clustering of activated microgli a expressing strongly enhanced levels of CD11b/c and MI-IC class TI wa s a feature of the GvHD-affected CNS, and despite the paucity of T lym phocytes present, activated microglial cell clusters mere invariably i ntimately associated with these T cells. Moreover, 70% of T cells in t he CNS were associated with single or clustered MHC class II+ microgli a, and interacting cells were predominantly deep within the tissue par enchyme, Approximately 3.7% of the microglia that were freshly isolate d from the GvHD-affected CNS were cycling, and proliferating cell nucl ear Ag-positive microglia were detected in situ. Microglia from GvHD-a ffected animals sorted to purity by dow cytometry and cultured, extend ed long complex processes, exhibited spineous processes, and were phag ocytic and highly motile, These outcomes are consistent with direct ti ssue macrophage-T cell interactions in situ that lead to activation, p roliferation, and expansion of the responding tissue-resident cell.