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Robert Endres^*, Marat B. Alimzhanov, Thomas Plitz^*, Agnes Fütterer^*, Marie H. Kosco-Vilbois, Sergei A. Nedospasov^||, Klaus Rajewsky, and Klaus Pfeffer^*

From the ^* Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, D-81675 Munich, Germany; the Institute for Genetics, University of Cologne, D-50931 Cologne, Germany; Serono Pharmaceutical Research Institute, Plan-les-Ouates, CH-1228, Switzerland; and the ^|| Engelhardt Institute of Molecular Biology and Belozersky Institute of Physico-Chemical Biology, 117984 Moscow, Russia

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) , 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.

Key Words: lymphotoxin • tumor necrosis factor • bone marrow transfer • follicular dendritic cell • germinal center

The continuous and generous support of H. Wagner is greatly appreciated. The authors thank E. Schaller, U. Huffstadt, S. Weiss, and K. Mink for expert technical assistance. The authors are also grateful to H.R. Rodewald and G. Kollias for providing Ly5.1⁺ C57BL/6 and TNF^–/– mice, respectively, and thank H. Neubauer, T. Novobrantseva, S. Scheu, and H. Häcker for critical reading of the manuscript and for scientific advice.

R. Endres and M.B. Alimzhanov contributed equally to this work.

Abbreviations used: AP, alkaline phosphatase; FDC, follicular dendritic cell; GC, germinal center; LT, lymphotoxin; BCR, B cell receptor; PNA, peanut agglutinin.

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