Bordmann for excellent technical support. of the spleen, location of B cells, the lack of an FDC network, nor the antibody response in TNFR1?/? mice. These results argue for a crucial role of TNFR1 expression on nonhematopoietic cells for the maintenance of the splenic architecture and proper B cell location. In addition, the lack in development of an FDC network after adoptive transfer suggests that either FDCs are not of bone marrow origin or that they depend on signals from nonhematopoietic cells for maturation. The immune system often requires the cognate interactions of T cells, B cells, and antigen-presenting cells to respond to invading antigens/pathogens (1). Rabbit polyclonal to PARP A primary B cell follicle contains surface (s)IgM+IgD+ resting recirculating B cells and follicular dendritic cells (FDCs)1. A secondary B cell follicle is composed of a follicular mantle containing sIgM+IgD+ resting B cells and a germinal center (GC) composed of centroblasts, centrocytes, activated CD4+ memory T cells, and FDCs (2, 3). In addition, a third compartment, the marginal zone, observed in spleen, contains a subset of nonrecirculating sIgMhighIgDlow B cells (4, 5), marginal zone macrophages, as well as marginal metallophilic macrophages (6C8). GCs Valerylcarnitine are sites of B cell activation in secondary lymphoid tissues (9) and FDCs represent the major nonlymphoid cellular component of a GC, retaining the antigen as an immune complex and providing a variety of costimulatory signals. Within the GC, the B cells closely interact with FDCs and T cells, providing both stimuli to the B cells that prevent their entry into apoptosis and promote their differentiation into memory cells or Valerylcarnitine plasma Valerylcarnitine cells (10). FDCs are thought to be required to support formation and maturation of GCs (3, 11, 12). In support of this concept, both FDC clusters and GCs are absent from the spleens of immunized lymphotoxin Cdeficient (LT-?/?), TNF-?/?, and TNFR1?/? mice (13C15). TNF- and LT- bind to the same receptors: TNFR1 (P55/CD120a) and TNFR2 (P75/CD120b) (16). In addition, when a LT- monomer trimerizes with two identical LT- subunits, the heterotrimers bind to a third type of receptor, LT-R (17). Mice with targeted disruption of the LT- gene manifest congenital absence of LNs Valerylcarnitine and Peyer’s patches (18, 19). The splenic white pulp is reduced and lacks clearly defined B and T cell compartments. Mice deficient for another TNFR1 ligand, TNF-, also lack GCs and FDCs (15). TNFR1?/? mice retain a normal layer of marginal metallophilic macrophages, yet they cannot form an organized FDC network and GCs (14). Since no such defect can be observed in TNFR2?/? mice (13, 20), the activity to form GC and FDC networks in response to TNF- homotrimers is most probably signaled exclusively through the TNFR1. Distinct signals regulate the formation of discrete B and T cell zones in the splenic white pulp and LNs (21). T and B cell segregation in the splenic white pulp requires expression of LT- and is independent of TNFR1 (21). Furthermore, activation of B cells to form GC-like structures of peanut agglutinin (PNA)-binding cells can occur in the mesenteric LNs of LT-?/? and TNFR1?/? mice, but not in their spleens (21). But, strikingly, both LT-?/? and TNFR1?/? mice lack FDCs in both LNs and spleen (21). Here we report that a significant number of plasma cells were abnormally located in the periarteriolar lymphoid sheaths (PALS) of the TNFR1?/? mice. Neither wild-type bone marrow (WT-BM) nor wild-type fetal liver (WT-FL) transplantation could normalize the distribution pattern of plasma cells in TNFR1?/? spleen. In contrast to LT-?/? mice, the spleen architecture of TNFR1?/? mice, including GC and FDC networks, also could not be rescued by transplantation of wild-type hematopoietic precursors. Taken together, our findings illustrate that TNFR1 expressed by nonhematopoietic elements is essential for proper distribution of B cells, de novo plasma cells, and formation of FDC networks. Materials and Methods Mice. C57BL/6 (Ly 5.1 and Ly 5.2 strains) and hybrid 129 Sv C57BL/6 mice were bred and maintained under specific pathogen-free conditions in the animal facility of the Basel Institute for Immunology (Basel, Switzerland) or in conventional animal facilities of the Cantonal Hospital.