Although the spleen will develop in mice deficient in any of the known TNF or TNFR family members, its architecture will be abnormal in many of these mutants (see Fig. 9.2). LT (most probably the membrane-bound LT-β) is required for the normal segregation of T-cell and B-cell zones in the spleen. TNF-α, binding to TNFR-I, also contributes to the organization of the white pulp: when TNF-α signals are disrupted, B cells surround T-cell zones in a ring rather than forming discrete follicles, and the marginal zones are not well defined.
Perhaps the most important role of TNF-α and TNFR-I in lymphoid organ development is in the development of FDCs, as these cells are lacking in mice with knockouts of either TNF-α or TNFR-I (see Fig. 9.2). The knockout mice do have lymph nodes and Peyer’s patches, because they express LTs, but these structures lack FDCs. LT-β is also required for FDC development: mice that cannot form LT-β or signal through its receptor lack normal FDCs in the spleen and any residual lymph nodes. Unlike the disruption of lymph-node development, the disorganized lymphoid architecture in the spleen is reversible if the missing TNF-family member is restored. B cells are the likely source of the LT-β, because normal B cells can restore FDCs and follicles when transferred to RAG-deficient recipients (which lack lymphocytes).
9-3 T and B cells are partitioned into distinct regions of secondary lymphoid tissues by the actions of chemokines.
Circulating T and B cells seed secondary lymphoid tissues from the blood by a common route, but are then directed into their respective compartments under the control of distinct chemokines that are produced by both stromal cells and bone marrow-derived cells resident in the Tand B-cell zones (Fig. 9.3). The localization of T cells into T-cell zones involves two chemokines, CCL19 (MIP-3β) and CCL21 (secondary lymphoid chemokine, SLC). Both of these bind the receptor CCR7, which is expressed by T cells; mice that lack CCR7 do not form normal T-cell zones and have impaired primary immune responses. CCL21 is produced by stromal cells of T-cell zones in secondary lymphoid tissues, and is displayed on endothelial cells of high endothelial venules (HEVs). Another source of CCL21 is interdigitating dendritic cells, which also produce CCL19 and are prominent in T-cell zones. Indeed, dendritic cells themselves express CCR7 and will localize to secondary lymphoid tissues even in RAG-deficient mice, which lack lymphocytes and therefore defined T-cell zones. Thus, during normal lymph-node development, the T-cell zone might be organized first through the attraction of dendritic cells and T cells by CCL21 produced by stromal cells. This organization would then be reinforced by CCL21 and CCL19 secreted by resident dendritic cells, which in turn attract more T cells and migratory dendritic cells.
CXCL13B cells induce the differentiation of follicular dendritic cells, which in turn secrete the chemokine CXCL13 to attract more B cells B cells are initially attracted into the developing lymph node by the same chemokines