The long-range goal of this program is to define the immunobiology of the macrophage. Central to achieving this goal is to understand the basis for macrophage functional and phenotypic diversity. The immediate object of the proposed work is to determine whether macrophage diversity is the result of the differentiation of a single lineage of cells or, rather, is clonal. I will exploit our ability to clone and expand macrophages from individual progenitors to populations containing sufficient numbers of cells for phenotypic and functional analyses. Using the mouse spleen as the experimental model, I will determine (i) if different immunologic accessory cell functions reside in different clones of macrophages, (ii) if it is possible to immortalize cloned populations of splenic macrophages while retaining their distinct functional properties, (iii) if selected homeostatic and host-defense functions of splenic macrophages reside in distinct subpopulations of cells, (iv) if it is possible to associate macrophage surface phenotype with macrophage function, (v) the location in the spleen, of phenotypically distinct macrophage populations and (vi) if phenotypic and functionally distinct macrophage populations are linearly independent. In addition to their roles in microbial and neoplastic host-defense as well as in homeostasis, macrophages are now recognized as having important pathologic activities in numerous human inflammatory diseases, in arteriosclerosis and, possibly, multiple sclerosis. Furthermore, monocytes/macrophages appear to be important in latent infection with the human immunodeficiency virus (HIV) and may be responsible for the in vivo dissemination of the virus to, for example, the central nervous system. If these and other activities of macrophages are limited to distinct subpopulations of cells, then the information gained from this study may make it possible to selectively manipulate them to therapeutic advantage.