The long-range goal of this program is to define and developmental immunobiology of macrophages. Central to achieving this goal are studies to clarify the basis of macrophage functional and phenotypic heterogeneity by determining whether this diversity is the result of stage of differentiation of a single lineage of cells or is clonal. In previous work, I used T cell hybridomas and lines to test for the presence, in the mouse spleen, of functionally distinct subsets of antigen-presenting macrophages and to determine the basis for differences in antigen- presenting phenotype. The present proposal builds on the results supporting the original hypothesis: that different populations of macrophage precursors in the spleen give rise to progeny with different antigen-presenting phenotypes for naive and memory CD4 + and CD8 + T cells. Using primary clones of splenic macrophages and a panel of cell lines derived from such clones, I intend to; (i) identify macrophage subsets with antigen-presenting activity for naive T cells and define the basis for the differences in the antigen-presenting phenotypes, (ii) determine whether the homeostatic function of splenic macrophages is restricted to a distinct subset of cells, (iii) determine if separate subsets of macrophage precursor cells yield progeny with different constitutive antigen-presenting phenotypes and homeostatic functions, (iv) locate subsets of the macrophages in the mouse spleen, and (v) establish the developmental relationships among the different precursor subsets giving rise to macrophages with different antigen-presenting phenotypes and homeostatic functions. Knowledge gained from this study will be of both fundamental and clinical interest. Once the basis of macrophage precursor heterogeneity is understood, and we acquire the ability to detect different subsets of these cells in situ, it should be possible to develop means to selectively manipulating these cells to the therapeutic advantage of the host.
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