Mature Follicular Dendritic Cell Networks Depend on Expression of Lymphotoxin β Receptor by Radioresistant Stromal Cells and of Lymphotoxin β and Tumor Necrosis Factor by B Cells

The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that the cytokines tumor necrosis factor (TNF), lymphotoxin (LT) α, and LTβ, as well as their receptors TNF receptor p55 (TNFRp55) and LTβR play essential roles in the development of GCs. To establish in which cell types expression of LTβR, LTβ, and TNF is required for GC formation, LTβR^−/−, LTβ^−/−, TNF^−/−, B cell–deficient (BCR^−/−), and wild-type mice were used to generate reciprocal or mixed bone marrow (BM) chimeric mice. GCs, herein defined as peanut agglutinin–binding (PNA⁺) clusters of centroblasts/centrocytes in association with follicular dendritic cell (FDC) networks, were not detectable in LTβR^−/− hosts after transfer of wild-type BM. In contrast, the GC reaction was restored in LTβ^−/− hosts reconstituted with either wild-type or LTβR^−/− BM. In BCR^−/− recipients reconstituted with compound LTβ^−/−/BCR^−/− or TNF^−/−/BCR^−/− BM grafts, PNA⁺ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent. Thus, development of splenic FDC networks depends on expression of LTβ and TNF by B lymphocytes and LTβR by radioresistant stromal cells.