title: ICOS, CD40, and lymphotoxin beta receptors signal sequentially and interdependently to initiate a germinal center reaction.
abstract: Germinal center (GC) responses to T-dependent Ags require effective collaboration between Th cells, activated B cells, and follicular dendritic cells within a highly organized microenvironment. Studies using gene-targeted mice have highlighted nonredundant molecules that are key for initiating and maintaining the GC niche, including the molecules of the ICOS, CD40, and lymphotoxin (LT) pathways. Signaling through ICOS has multiple consequences, including cytokine production, expression of CD40L on Th cells, and differentiation into CXCR5(+) follicular Th cells, all of which are important in the GC reaction. We have therefore taken advantage of ICOS(-/-) mice to dissect which downstream elements are required to initiate the formation of GC. In the context of a T-dependent immune response, we found that GC B cells from ICOS(-/-) mice express lower levels of LTalphabeta compared with wild-type GC B cells in vivo, and stimulation of ICOS on T cells induces LTalphabeta on B cells in vitro. Administration of agonistic anti-LTbeta receptor Ab was unable to restore the GC response in ICOS(-/-) mice, suggesting that additional input from another pathway is required for optimal GC generation. In contrast, treatment with agonistic anti-CD40 Ab in vivo recovered GC networks and restored LTalphabeta expression on GC B cells in ICOS(-/-) mice, and this effect was dependent on LTbeta receptor signaling. Collectively, these data demonstrate that ICOS activation is a prerequisite for the up-regulation of LTalphabeta on GC B cells in vivo and provide a model for cooperation between ICOS, CD40, and LT pathways in the context of the GC response.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
authors.forename: Frances
authors.initials: F
authors.lastname: Vu
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.forename: Carl F
authors.initials: CF
authors.lastname: Ware
authors.forename: Tak
authors.initials: T
authors.lastname: Mak
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Gommerman
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000502:physiology*; D002645:Chickens; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D060889:Inducible T-Cell Co-Stimulator Protein; D053259:Lymphotoxin beta Receptor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008233:Lymphotoxin-alpha / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009596:Nitrophenols / Q000008:administration & dosage / Q000276:immunology; D010648:Phenylacetates; D015398:Signal Transduction / Q000276:immunology*; D005719:gamma-Globulins / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D019013:CD40 Antigens; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D009596:Nitrophenols; D010648:Phenylacetates; D005719:gamma-Globulins; C026242:4-hydroxy-5-nitrophenyl acetic acid