Before discussing how T cells and B cells become partitioned into their respective zones in secondary lymphoid organs, we shall briefly look at how these organs develop in the first place. Lymphatic vessels are formed during embryonic development from endothelial cells that originate in blood vessels. Some endothelial cells in the early venous system begin to express the homeobox transcription factor Prox1. These cells bud from the vein, migrate away, and reassociate to form a parallel network of lymphatic vessels. Mice lacking Prox1 have normal arteries and veins, but fail to form a lymphatic system, showing this factor to be critical in establishing the identity of lymphatic endothelium. As the lymphatic vessels form, hematopoietic cells called lymphoid tissue inducer (LTi) cells arise in the fetal liver and are carried in the bloodstream to sites of prospective lymph nodes and Peyer’s patches. LTi cells initiate the formation of lymph nodes and Peyer’s patches by interacting with stromal cells and inducing the production of cytokines and chemokines, which recruit other lymphoid cells to these sites. Members of the tumor necrosis factor (TNF)/ TNF receptor (TNFR) family of cytokines turn out to be critically involved in the interactions between LTi cells and stromal cells.
The role of this family of cytokines in the formation of secondary lymphoid organs has been demonstrated in a series of studies involving knockout mice in which either the TNF-family ligand or its receptor was inactivated (Fig. 9.2). These knockout mice have complicated phenotypes, which is partly due to the fact that individual TNF-family proteins can bind to multiple receptors and, conversely, many receptors can bind more than one ligand. In addition, it seems clear that there is some overlapping function or cooperation between TNF-family proteins. Nonetheless, some general conclusions can be drawn.
Lymph-node development depends on the expression of TNF-family proteins known as the lymphotoxins (LTs), and different types of lymph nodes depend on signals from different LTs. LT-α3, a soluble homotrimer of the LT-α chain, supports the development of cervical and mesenteric lymph nodes, and possibly lumbar and sacral lymph nodes. All these lymph nodes drain mucosal sites. LT-α3 probably exerts its effects by binding to TNFR-I. The membrane-bound heterotrimer consisting of two molecules of LT-α and one molecule of the distinct transmembrane protein LT-β (that is, LT-α2:β1), often known as LT-β, binds only to the LT-β receptor and supports the development of all the other lymph nodes. Peyer’s patches also do not form in the absence of LT-β. The effects of the LT knockouts are not reversible in adult animals; there are certain critical developmental periods during which the absence or inhibition of these LT-family proteins will permanently prevent the development of lymph nodes and Peyer’s patches.
LTi cells express LT-β, which engages the LT-β receptors on stromal cells in the prospective lymphoid site, activating the non-canonical NFκB pathway