Generation of Splenic Follicular Structure and B Cell Movement in Tumor Necrosis Factor–deficient Mice

Secondary lymphoid tissue organogenesis requires tumor necrosis factor (TNF) and lymphotoxin α (LTα). The role of TNF in B cell positioning and formation of follicular structure was studied by comparing the location of newly produced naive recirculating and antigen-stimulated B cells in TNF(−/−) and TNF/LTα(−/−) mice. By creating radiation bone marrow chimeras from wild-type and TNF(−/−) mice, formation of normal splenic B cell follicles was shown to depend on TNF production by radiation-sensitive cells of hemopoietic origin. Reciprocal adoptive transfers of mature B cells between wild-type and knockout mice indicated that normal follicular tropism of recirculating naive B cells occurs independently of TNF derived from the recipient spleen. Moreover, soluble TNF receptor–IgG fusion protein administered in vivo failed to prevent B cell localization to the follicle or the germinal center reaction. Normal T zone tropism was observed when antigen-stimulated B cells were transferred into TNF(−/−) recipients, but not into TNF/LTα(−/−) recipients. This result appeared to account for the defect in isotype switching observed in intact TNF/LTα(−/−) mice because TNF/LTα(−/−) B cells, when stimulated in vitro, switched isotypes normally. Thus, TNF is necessary for creating the permissive environment for B cell movement and function, but is not itself responsible for these processes.