The long-range goal of this program is to define the roles of microglia in the initiation and expression of immune reactions in the central nervous system. The program will be aided by our ability to clone and expand microglia from individual progenitor cells in the mouse brain to populations containing sufficient numbers of cells for molecular, surface immunophenotypic and functional analyses. Using this approach, we have detected subsets of microglia differing in their ability present alloantigen to naive CD8+ T-cells and exogenous antigens to memory CD4+ T- cells. The proposed work will extend these findings to additional T cell subsets. Specifically, we will: (i) Identify subsets of microglia with distinct antigen-presenting phenotypes for naive and memory CD4+ and CD8+ T cells, ascertain if each is derived from separate progenitor cells and, established the progenitor frequencies and the stability of each phenotype; (ii) Determine the basis for the different antigen-presenting phenotypes by identifying the accessory and costimulatory molecules that contribute to the activity of each; and (iii) Relate microglial surface immunophenotype to antigen-presenting phenotype, and begin to define the tissue distribution and cellular associations of the different phenotypes in normal and disease brain tissue. The knowledge gained from this study will be both of fundamental interest and clinical relevance. An understanding of the basis for the distinct antigen-presenting activities of microglia, and the ability to detect these cells in situ may make it possible to develop means to selectively manipulate them to the therapeutic advantage of the host.
