title: Signaling through TNF receptor p55 in TNF-alpha-deficient mice alters the CXCL13/CCL19/CCL21 ratio in the spleen and induces maturation and migration of anergic B cells into the B cell follicle.
abstract: The organization of secondary lymphoid tissues into distinct T and B cell compartments supports proper regulation of an immune response to foreign Ags. In the splenic white pulp, this compartmentalization is also thought to be important in the maintenance of B cell tolerance. Using lymphotoxin-alpha-(LT-alpha)-, TNF-alpha-, or TNFRp55-deficient mice, all with disrupted splenic architecture, we tested whether normal T/B segregation and/or intact follicular 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 positioning to the T/B interface. Providing a TNF-alpha signal in TNF-alpha(-/-) mice by systemic administration of an agonist anti-TNFRp55 mAb induces the maturation of the anti-dsDNA B cells and their movement away from the T cell area toward the B cell area. Additionally, the agonist Ab induces changes in the follicular environment, including FDC clustering, up-regulation of the CXC chemokine ligand CXCL13, and down-regulation of the CC chemokine ligands CCL19 and CCL21. Therefore, this study suggests that a balance between 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.
authors.affiliation: Center for Immunology and Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: L
authors.initials: L
authors.lastname: Mandik-Nayak
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.forename: K C
authors.initials: KC
authors.lastname: Sheehan
authors.forename: J
authors.initials: J
authors.lastname: Erikson
authors.forename: D D
authors.initials: DD
authors.lastname: Chaplin
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000378:metabolism; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000378:metabolism; D017635:Clonal Anergy / Q000235:genetics*; D020566:Dendritic Cells, Follicular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007106:Immune Sera / Q000008:administration & dosage / Q000502:physiology; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D007146:Immunoglobulin lambda-Chains / Q000096:biosynthesis / Q000235:genetics; D016130:Immunophenotyping; D007275:Injections, Intravenous; D008233:Lymphotoxin-alpha / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency* / Q000235:genetics*
chemical_list: D000974:Antibodies, Antinuclear; D015703:Antigens, CD; C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; D019742:Chemokines, CC; D019743:Chemokines, CXC; C486386:Cxcl13 protein, mouse; D007106:Immune Sera; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007146:Immunoglobulin lambda-Chains; D008233:Lymphotoxin-alpha; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha