Signaling through TNF receptor p55 in TNF-alpha-deficient mice alters the CXCL13/CCL19/CCL21 ratio in the spleen and induces maturation and migrationof anergic B cells into the B cell follicle

The organization of secondary lymphoid tissues into distinct T and B cell c ompartments supports proper regulation of an immune response to foreign Ags . In the splenic white pulp, this compartmentalization is also thought to b e important in the maintenance of B cell tolerance. Using lymphotoxin-alpha -(LT-alpha)-, TNF-alpha-, or TNFRp55-deficient mice, all with disrupted spl enic architecture, we tested whether normal T/B segregation and/or intact f ollicular structure are necessary for the maintenance of anti-dsDNA B cell anergy. This study demonstrates that anti-dsDNA B cells remain tolerant in LT-alpha (-/-), TNF-alpha (-/-), and TNFRp55(-/-) mice; however, TNF-alpha or a TNF-alpha -dependent factor is required for their characteristic posit ioning to the T/B interface. Providing a TNF-alpha signal in TNF-alpha (-/- ) mice by systemic administration of an agonist anti-TNFRp55 mAb induces th e maturation of the anti-dsDNA B cells and their movement away from the T c ell area toward the B cell area. Additionally, the agonist Ab induces chang es in the follicular environment, including FDC clustering, up-regulation o f the CXC chemokine ligand CXCL13, and down-regulation of the CC chemokine ligands CCL19 and CCL21. Therefore, this study suggests that a balance betw een B and T cell tropic chemokine signals may be an important mechanism for positioning anergic B cells at the T/B interface of the splenic white pulp .