Development and Differentiation of Microglia Cells

Microglia cells of the central nervous system are local antigen presenting cells of the central nervous system which show a remarkably little turnover with blood borne macrophages. Several lines of evidence suggest that microglia cells are not terminally differentiated along the myeloid lineage. This immature/undifferentiated state could contribute to the immune privilege of the central nervous system. Several open questions remain: How different are microglia cells from other tissue macrophages? Do microglia cells represent a different developmental lineage than other tissue macrophages? Is the graded response of microglia to trauma, degeneration, infection and inflammation associated with differentiation of these cells? The proposed project will address these questions.

Microglia cells comprise up to 20% of the non-neuronal cell population in brain and spinal cord and are ubiquitously distributed throughout the CNS parenchyma. The parenchymal microglia cells play an important role during inflammation, infection, trauma, ischemia, and degeneration of the CNS. Microglia cells are immature myeloid precursor cells which can differentiate to dendritic cells or macrophages in the presence of appropriate stimuli. We studied the differentiation of these cells in vivo and in vitro, and analyzed the consequences of this differentiation for immune responses within the CNS. So far, we obtained the following key results: 1. Microglia-derived semi-mature and mature dendritic cells leave the CNS via the blood stream and home to T cell zones of lymphatic organs. Since these cells are able to capture antigens, they are ideal tools to carry antigens from the CNS to spleen and lymph nodes, and to activate naive and memory CNS antigen-specific T lymphocytes. Doing this, microglia-derived dendritic cells could trigger both onset and relapses of MS sclerosis, and could provide a key target for the treatment of this disease. 2. In the myelin-degenerative CNS, microglia cells differentiate to dendritic cells. The presence of such cells in the degenerative CNS is particularly interesting, since we could show that CD4+ and CD8+ T cells preferentially infiltrate areas of myelin degeneration and microglia cell stimulation in the otherwise intact organism, and that interactions between MHC class II+ microglia cells and infiltrating T cells might represent the point of transition between harmless immune cell infiltration and the onset of inflammation. We could also show that the myelin degenerative, microglia-activating CNS alters the extent, cellular composition and location of inflammatory cells in the inflamed CNS.