IgG2a-Mediated Enhancement of Antibody and T Cell Responses and Its Relation to Inhibitory and Activating Fcγ Receptors

Abstract

A number of studies in experimental animal models point to an important role of FcγRs in autoimmunity and allergy. In this study, we investigate how the production of IgG, an early step in the chain of events leading to inflammation, is regulated by activating and inhibitory FcγRs. IgG Abs are known to feedback-enhance Ab responses to soluble Ags, and this effect requires activating FcγRs. To test proliferation of Th cells, mice were adoptively transferred with CD4+ T cells expressing a transgenic OVA-specific TCR before immunization with IgG2a anti-2,4,6-trinitrophenyl (TNP) plus OVA-TNP or with OVA-TNP alone. IgG2a induced a significant increase in OVA-specific T cell numbers, which preceded the OVA-specific Ab response and was dependent on the FcRγ chain. The role of the inhibitory FcγRIIB in Ab responses was studied in mice lacking this receptor. Although IgG2a enhanced primary Ab responses, development of germinal centers, and immunological memory in wild-type mice, enhancement was markedly stronger in FcγRIIB−/− mice. The presented data are compatible with the hypothesis that the mechanism behind IgG2a-mediated up-regulation of Ab responses involves increased Ag presentation to CD4+ T cells by FcγR+ APCs. Our observations also illustrate the intricate immunoregulatory role of IgG Abs. On the one hand, they enhance Ab responses via activating FcγRs, and on the other hand, they set an upper limit for the same Ab response via FcγRIIB.

A Novel B Cell-Mediated Transport of IgE-Immune Complexes to the Follicle of the Spleen

“…3J) shows a typical example of T-B cell interactions. In agreement with previous data (9,19), OVA-specific T cells proliferated vigorously 72 h after immunization with IgE/Ag (Fig. 3F) or IgG2a/Ag (Fig.…”

“…9 and 19) as well as the ability to enhance Ab responses (9,19) are similar after immunization with IgE-and IgG2a-complexed Ag; the two Ab classes clearly use different mechanisms to achieve these effects. As described previously, IgE is dependent on CD23 expressed on B cells (18,19) and IgG2a requires activating Fc␥Rs expressed on a bone marrow-derived cell other than the B cell (which lacks activating Fc␥Rs) (7)(8)(9). Another difference, first described herein, is that IgG2a-Ag complexes are not transported as rapidly into the follicles as IgE-Ag complexes (Fig.…”

“…To visualize the splenic localization of Ag, mice were immunized with biotinylated Ag alone, IgE/Ag, or IgG2a/Ag. Immune complexes containing IgG2a were included for comparison because IgG2a enhances T cell proliferation and Ab production in a similar manner as does IgE, but uses activating Fc␥Rs instead of CD23 (9,11). In IgE/Ag-immunized mice, essentially all Ag localized to the primary follicles within 30 min (Fig.…”

“…Monoclonal IgE anti-TNP (IGELb4) (46) and IgG2a anti-TNP (C4007B4, 7B4) (11) were purified and stored as previously described (9,19). For flow cytometry and immunostainings, the following mAbs from BD Pharmingen were used: PE-labeled anti-CD4 (GK1.5), PE-or FITC-labeled anti-CD23 (B3B4), FITC-or PE-labeled anti-CD45R/B220 (RA3-6B2), FITClabeled anti-CD19 (1D3), allophycocyanin-or R-PE-labeled streptavidin, and PE-labeled anti-CD21 (7G6).…”

“…Enhancement by IgG3 is dependent on C (6) whereas IgG1-, IgG2a-, and IgG2b-mediated enhancement relies on activating Fc␥Rs expressed on a bone marrowderived cell (7,8). The inhibitory receptor for IgG, Fc␥RIIB, exerts a negative influence on enhancement mediated by IgG1, IgG2a, or IgG2b as demonstrated by the "superenhancement" caused by these isotypes in mice lacking Fc␥RIIB (7,9). IgG enhances not only primary Ab responses, but also secondary Ab responses (10,11), the formation of germinal centers (GCs) 3 (9,12), somatic hypermutation (13), and proliferation of specific CD4 ϩ T cells (9).…”