Marginal Zone B Cells Transport IgG3-Immune Complexes to Splenic Follicles

Abstract

Ag administered together with specific IgG3 induces a higher Ab response than Ag administered alone, an effect requiring the presence of complement receptors 1 and 2 (CR1/2). In this study, we have investigated the fate of Ag, the development of germinal centers (GCs), and the Ab response after i.v. administration of IgG3 anti-trinitrophenyl (TNP) in complex with OVA-TNP. After 2 h, OVA-TNP was detected on marginal zone (MZ) B cells, and a substantial amount of Ag was detected in splenic follicles and colocalized with follicular dendritic cells (FDCs). After 10 d, the percentage of GCs and the IgG responses were markedly higher than in mice immunized with uncomplexed OVA-TNP. The effects of IgG3 were dependent on CR1/2 known to be expressed on B cells and FDCs. Using bone marrow chimeric mice, we demonstrate that an optimal response to IgG3-Ag complexes requires that CR1/2 is expressed on both cell types. These data suggest that CR1/2+ MZ B cells transport IgG3-Ag-C complexes from the MZ to the follicles, where they are captured by FDCs and induce GCs and IgG production. This pathway for initiating the transport of Ags into splenic follicles complements previously known B-cell dependent pathways where Ag is transported by 1) MZ B cells, binding large Ags-IgM-C complexes via CR1/2; 2) recirculating B cells, binding Ag via BCR; or 3) recirculating B cells, binding IgE-Ag complexes via the low-affinity receptor for IgE, CD23.

IgE-mediated enhancement of CD4+ T cell responses requires antigen presentation by CD8α− conventional dendritic cells

“…Ag enters the blood, forms a complex with IgE and binds to CD23 + B cells637 (or, hypothetically, a pathogen expressing the appropriate lectins binds directly to CD23 + B cells). These recirculating B cells have access to splenic follicles and substantial amounts of Ag is found on follicular B cells in the spleen, and is detected in splenic follicles, 0.5–4 h after immunization6 (Fig.…”

“…IgG anti-OVA ELISA was performed as described37. Construction of standard curves and calculations of the concentration of IgG anti-OVA were performed with SOFTmax software (Molecular Devices, Sunnyvale, CA).…”

IgG3-antigen complexes are deposited on follicular dendritic cells in the presence of C1q and C3

“…Passively administered IgG3 enhances antibody responses to small proteins such as ovalbumin (OVA) or bovine serum albumin (BSA) 24–26 . This ability is impaired in Cr2 KO mice 24, 26 and in mice partially depleted of C3 by treatment with cobra venom factor 24 , but is unperturbed in mice selectively lacking FcγRI 25 , identified as the IgG3-binding Fc-receptor 27 , and in mice lacking all activating FcγRs owing to lack of the common FcRγ chain 24 . Passive administration of specific IgG3 enhances localization of antigen to splenic B cell follicles and binding of antigen to MZ B cells 26 .…”

“…This ability is impaired in Cr2 KO mice 24, 26 and in mice partially depleted of C3 by treatment with cobra venom factor 24 , but is unperturbed in mice selectively lacking FcγRI 25 , identified as the IgG3-binding Fc-receptor 27 , and in mice lacking all activating FcγRs owing to lack of the common FcRγ chain 24 . Passive administration of specific IgG3 enhances localization of antigen to splenic B cell follicles and binding of antigen to MZ B cells 26 . When MZ B cells are dislocated from the MZ by treatment with FTY720, an antagonist to the sphingosine 1-phosphate receptor S1P1, localization of antigen in the follicles is disrupted.…”

“…This suggests that transport of IgG3-antigen complexes by MZ B cells explains IgG3-induced localization of antigen to follicles. IgG3 is unable to increase the localization of antigen to follicles in Cr2 KO mice, and optimal enhancement of antibody responses requires that CR1/2 are expressed on both B cells and FDC 26 . Our previous report indicated that IgG3-antigen co-localized with FDC 26 .…”