Summary Recent studies report that B cells acquire large lymph-borne antigens and immune complexes directly from subcapsular sinus macrophages while small antigens appear to diffuse directly into the B cell follicles. To directly compare entrance of large and small Ags into the follicles, we used multiphoton intravital microscopy to track drainage of Ag into the peripheral lymph nodes and subsequent encounter by B cells and follicular dendritic cells in the underlying follicles. We find that a system of conduits extends into the follicles and mediates delivery of small antigens to cognate B cells and follicular dendritic cells. The follicular conduits provide an efficient and rapid mechanism for delivery of small antigens to B cells, which directly contact the CXCL13 chemokine-enriched conduits. By contrast, large antigens were bound by subcapsular sinus macrophages and subsequently transferred to follicular B cells as previously reported.

Interaction between different types of hematopoietic cells is essential for proper functioning of the immune system. For instance, the cytokines produced by antigen-presenting dendritic cells will determine the type of T cell response that is induced. However, hematopoietic cells are also strongly influenced by the surrounding nonhematopoietic cells. The cells that form these microenvironments are collectively called stromal cells. Here, we focus on the stromal cells present within secondary lymphoid organs and discuss their importance for various aspects of the immune system.

The lymphoid compartment of lymph nodes is impermeable to many molecules that are delivered via afferent lymphatic vessels. In the lymphoid compartment, fibroblast reticular cells form an interconnected network-the conduit system. This network has a structural function supporting tightly packed lymphocytes and antigen-presenting cells; however, it also has an important function as a molecular sieve, since it contains tubules that are the only entry point for fluid and allow only small molecules and particles (including antigens) to flow along the network. This size exclusion may prevent pathogens entering the blood from lymph. Dendritic cells can sample antigens from the conduit system and present them to nearby lymphocytes; this may be particularly important in initiating immune responses. The importance of larger antigen transport via macrophages or other cells is unclear. Lymphocytes and antigen-presenting dendritic cells actively move and interact along the conduit system, perhaps in response to chemokines or cytokines transported by the conduit system; these molecules may also be transported to high endothelial venules and regulate the attraction of blood leukocytes to the lymph nodes. The conduit system is also important for fluid distribution between afferent lymphatics and blood, but the mechanisms are not yet established.

The complement system is a family of proteins that is involved in both innate and adaptive immunity. Complement receptors CD21 and CD35, which recognize activated products of C3 and C4, are predominantly expressed on B cells and follicular dendritic cells (FDCs) in the mouse. In this review, we focus on the role of FDC-expressed CD21 and CD35 in humoral immunity. They are the principle receptors for uptake and retention of immune complexes. In their absence, memory B-cell survival is markedly impaired. This is likely because of the lack of antigen but could also reflect a role for complement C3d ligand. How antigen is transported to FDCs remains an open question. In recent unpublished work using multiphoton intravital imaging, we found that small protein antigens presented in the lymph drain rapidly into B-cell follicles and are taken up by FDCs in a complement-dependent manner.