Fig. 9.2 The role of TNF family members in the development of peripheral lymphoid organs. The role of TnF family members in the development of peripheral lymphoid organs has been deduced mainly from the study of knockout mice deficient in one or more TnF-family ligands or receptors. some receptors bind more than one ligand, and some ligands bind more than one receptor, complicating elucidation of the effects of their deletion. (note that receptors are named for the first ligand known to bind them.) The defects are organized here with respect to the two main receptors, TnFr-I and the LT-β receptor, and their ligands, TnF-α and the lymphotoxins (LTs). note that in some cases, the losses of individual ligands out of several that bind the same receptor lead to different respective phenotypes, as indicated in the figure. This is due to the ability of the different ligands to bind different sets of receptors. The LT-α protein chain contributes to two distinct ligands, the trimer LT-α3 and the heterodimer LT-α2:β1, each of which acts through a distinct receptor. In general, signaling through the LT-β receptor is required for lymph-node and follicular dendritic cell (FdC) development and for normal splenic architecture, whereas signaling through TnFr-I is also required for FdCs and normal splenic architecture but not for lymph-node development.
Fig. 9.3 The development of secondary lymphoid organs is orchestrated by chemokines. The cellular organization of lymphoid organs is initiated by stromal cells and vascular endothelial cells, which secrete the chemokine CCL21 (first panel). dendritic cells with CCr7—a receptor for CCL21—are attracted to the site of the developing lymph node by CCL21 (second panel); it is not known whether at the earliest stages of lymph-node development immature dendritic cells enter from the bloodstream or via the lymphatics, as they do later in life. once in the lymph node, the dendritic cells express the chemokine CCL19, which is also bound by CCr7. Together, the chemokines secreted by stromal cells and dendritic cells attract T cells to the developing lymph node (third panel). The same combination of chemokines also attracts B cells into the developing lymph node (fourth panel). The B cells are able to either induce the differentiation of the nonleukocyte FdCs (which are a lineage distinct from the bone marrow-derived dendritic cells) or direct their recruitment into the lymph node. once present, the FdCs secrete CXCL13, a chemokine that is a chemoattractant for B cells. The production of CXCL13 drives the organization of B cells into discrete B-cell areas (follicles) around the FdCs and contributes to the further recruitment of B cells from the circulation into the lymph node (fifth panel).
(see Section 7-23). This induces the stromal cells to express adhesion molecules and chemokines such as CXCL13 (B-lymphocyte chemokine, BLC), which in turn recruits more LTi cells, which have receptors for these molecules, eventually generating large clusters of cells that will become lymph nodes or Peyer’s patches. The chemokines also attract cells such as lymphocytes and other hematopoietic-lineage cells with appropriate receptors to populate the forming lymphoid organ. The principles, and even some of the molecules, underlying the development of secondary lymphoid organs in the fetus are very similar to those that maintain the organization of lymphoid organs in the adult, as we shall see in the next section.