Lymphocyte proliferation in germinal centers (GC's) is thought to be triggered by antigen retained extracellularly on the surface of special "dendritic" cells. The anatomy and function of these cells have not been studied directly or in detail. We therefore examined mouse spleen GC's developing in response to sheep erythrocyte stimulation.We found that distinctive "follicular dendritic cells" (FDC's) were present in both the GC and adjacent mantle region of secondary follicles. The large, irregularly shaped nucleus, containing little heterochromatin, allowed for the light microscope (LM) identification of FDC's. By EM, the cell was stellate in shape sending out long, thin sheets of cytoplasm which could fold and coil into complex arrays. The processes were coated extracellularly by an amorphous electron-dense material of varying thickness, as well as particulates including variable numbers of virions. The FDC cytoplasm lacked organelles of active secretory and endocytic cells, such as well-developed rough endoplasmic reticulum (RER) and lysosomes. These anatomical features readily distinguished FDC's from other cell types, even those that were extended in shape.To pursue these descriptive findings, we injected three electron-dense tracers i.v. and sacrificed the mice 1 h-10 days thereafter. Colloidal carbon, colloidal thorium dioxide (cThO2), and soluble horseradish peroxidase (HRP) were actively sequestered into the vacuolar system of macrophages but were interiorized only in trace amounts by FDC's. Therefore, FDC's are not macrophages by cytologic and functional criteria. FDC's did display a unique property. Both colloidal carbon and thorium dioxide, which are nonimmunogens, could be visualized extracellularly on the cell surface for several days. The meaning of this is unclear, but the association of colloid with FDC's appeared to slow the movement of particulates through the extracellular space into the GC proper. FDC's were not readily identified in splenic white pulp lacking GC's. They must develop de novo then, possibly from novel dendritic cells that we have identified in vitro (Steinman, R. M., and Z.
The distribution of immune complexes has been studied in mouse spleen stimulated to contain many germinal centers (GC's). Horseradish peroxidase (HRP)-anti-HRP complexes were used as an appropriately precise and sensitive model. We were primarily interested in the relative abilities of three cell types to interact with complexes: lymphocytes, macrophages, and follicular dendritic cells (FDC's). The latter are distinctive, nonendocytic, stellate cells located primarily at the transition of mantle and GC zones of 2 ~ lymphoid follicles (Chen, L. L., J. C. Adams, and R. M. Steinman, 1978, J. Cell Biol. 77"148).Binding of immune complexes to lymphocytes could not be visualized in situ. Macrophages avidly interiorized complexes into lysosomes, but did not retain them extracellularly. In contrast, FDC's could retain HRP-anti-HRP extracellulady under appropriate conditions, but did not endocytose them. Cytochemical reactivity accumulated progressively on FDC's 1-6 h after administration of complexes i.v., remained stable in amount and location for 1 day, and then was progressively lost over a 1-to 5-day period.Several variables in the association of complexes with macrophages and FDC's were pursued. Only 1 /~g of complexed HRP had to be administered to visualize binding to both cell types. Macrophages interiorized complexes formed in a wide range of HRP/anti-HRP ratios, while FDC's associated with complexes formed in HRP excess only. Quantitative studies with [12SI]HRP-anti-HRP demonstrated that 20% of the splenic load of HRP associated with FDC's. Complexes formed with an F(ab')~ anti-HRP were distributed primarily in macrophages. When the levels of the third component of serum complement were depleted by prior treatment with cobra venom factor, uptake of complexes by macrophages was reduced some 50% whereas association with FDC's was abolished.The fact that antigen excess complexes are retained extracellularly strengthens the idea that they are immunogenic. Finally, the association of complexes with FDC's seems to retard the entry of antigen into the GC proper.J. CELL BIOLOGY 9 The Rockefeller University Press 9 0021-9525/78
We have identified and characterized a distinctive population of dendritic cells (DCs) in mouse spleen, lymph nodes, thymus, and liver. Dendritic cells can adhere to tissue culture surfaces but otherwise differ considerably from macrophages, the other major class of adherent cell. Morphological differences are evident by phase contrast and electron microscopy, and by cytochemistry. Dendritic cells exhibit little or no binding and phagocytosis of opsonized particles. During culture, they retain their unusual morphological features and surface markers, but lose the capacity to adhere. All DCs express and synthesize Ia antigens for several days in vitro, whereas only a subpopulation of mouse macrophages expresses Ia in all organs we have studied. Thus, DCs can be distinguished from macrophages in several independent and stable traits. Highly enriched preparations of the 2 cell types have been obtained. Spleen DCs are derived from bone marrow and are present in nude mice. Dendritic cells do not proliferate, but exhibit a rapid turnover. Other features in their life history are not known. We are studying the contribution of DCs to several immune responses. In all organs we have studied, they are powerful stimulators of the primary mixed leukocyte reaction. B cells, T cells, and macrophages from these organs are weak or inactive. Dendritic cells are potent accessory cells in T cell proliferative responses to mitogens and tuberculin antigens. These dendritic cells and Langer hans cells may belong to a similar lineage, but to date, Birbeck granules, surface A TPase, and binding of opsonized erythrocytes have not been demonstrated in spleen dendritic cells. However, in functional assays, both DCs and Langerhans cells synthesize Ia antigens and contribute to transplantation reactions, accessory cell function, and the development of contact sensitivity.
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