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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurology C Study Section (NEUC)
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St. Jude Children's Research Hospital
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Walker, W S (1999) Separate precursor cells for macrophages and microglia in mouse brain: immunophenotypic and immunoregulatory properties of the progeny. J Neuroimmunol 94:127-33
Havenith, C E; Askew, D; Walker, W S (1998) Mouse resident microglia: isolation and characterization of immunoregulatory properties with naive CD4+ and CD8+ T-cells. Glia 22:348-59
Sun, D; Whitaker, J N; Cao, L et al. (1998) Cell death mediated by Fas-FasL interaction between glial cells and MBP-reactive T cells. J Neurosci Res 52:458-67
Walker, W S; Castrucci, M R; Sangster, M Y et al. (1997) HEL-Flu: an influenza virus containing the hen egg lysozyme epitope recognized by CD4+ T cells from mice transgenic for an alphabeta TCR. J Immunol 159:2563-6
Sun, D; Hu, X; Liu, X et al. (1997) Expression of chemokine genes in rat glial cells: the effect of myelin basic protein-reactive encephalitogenic T cells. J Neurosci Res 48:192-200
Askew, D; Walker, W S (1996) Alloantigen presentation to naive CD8+ T cells by mouse microglia: evidence for a distinct phenotype based on expression of surface-associated and soluble costimulatory molecules. Glia 18:118-28
Askew, D; Havenith, C E; Walker, W S (1996) Heterogeneity of mouse brain macrophages in alloantigen presentation to naive CD8+ T cells as revealed by a panel of microglial cell lines. Immunobiology 195:417-30
Walker, W S; Gatewood, J; Olivas, E et al. (1995) Mouse microglial cell lines differing in constitutive and interferon-gamma-inducible antigen-presenting activities for naive and memory CD4+ and CD8+ T cells. J Neuroimmunol 63:163-74
Askew, D; Gatewood, J; Olivas, E et al. (1995) A subset of splenic macrophages process and present native antigen to naive antigen-specific CD4+ T-cells from mice transgenic for an alpha beta T-cell receptor. Cell Immunol 166:62-70
Olivas, E; Chen, B B; Walker, W S (1995) Use of the Pannell-Milstein roller bottle apparatus to produce high concentrations of the CSF-1, the mouse macrophage growth factor. J Immunol Methods 182:73-9