Induction of IgG3 secretion by interferon gamma: a model for T cell-independent class switching in response to T cell-independent type 2 antigens.

Abstract

SummaryT cell-independent type 2 (TI-2), in contrast to T-dependent, antigens stimulate the production of murine IgG3. To investigate a possible role for cytokines in mediating the induction of this IgG subclass, we established an in vitro polyclonal model system for studying TI-2 antigen-mediated B cell activation by using dextran-conjugated anti-IgD antibody (o~6-dex). We demonstrate that interferon "r (IFN-7) stimulates, and interleukin 4 inhibits, the expression of IgG3 by c~&dex-activated cells. The production of IFN-'r by non-T cells in response to bacterial products, possibly capsular polysaccharides, may provide an explanation underlying the ability of TI antigens, which are unable to directly stimulate T cell-derived cytokines to induce Ig isotype switching.ttle is known regarding the parameters that regulate the humoral immune response to T cell-independent type 2 (TI-2) I antigens. Such antigens, exemplified by the haptenated polysaccharides, are typically abundant in bacterial cell walls. Immunization of mice with this class of antigen, in contrast to T cell-dependent antigens, stimulates a significant increase in serum levels of antigen-specific IgG3 (1). Since Ig class switching is widely viewed as a process that is regulated by the release of T cell-derived cytokines, the ability of TI-2 antigens to stimulate IgG3 production is especially intriguing. In this regard, it is of interest that no cytokine has been described that regulates its synthesis in a selective and positive manner.The study of B cell responses to TI-2 antigens has been hampered by the low frequency of B cells specific for a given immunizing antigen. We recently described a model system in which resting murine mlgD + B cells are polyclonally activated in vitro in a manner similar to the specific antibody response mediated by the prototypical TI-2 antigen, TNPFicoll (2, 3). Thus, like TNP-Ficoll, multiple anti-IgD mAb molecules covalently linked to a high molecular weight dextran backbone induce resting B cells to proliferate in the absence of significant Ig production. The addition of a differentiation factor, such as IL-5, stimulates the secretion of large amounts of polyclonal Ig by dextran-conjugated anti-IgD an-1 Abbreviations used in this paper: o~-dex, dextran-conjugated anti-IgD antibody; TI-2, T cell-independent type 2.

Immuno- and Hepato-Toxicity of Dichloroacetic Acid in MRL+/+and B6C3F1Mice

“…The immunoglobulins IgG and IgM were increased in MRL +/+ mice following DCA treatment, suggesting immune activation in this strain. Only IgG 3 levels were increased significantly in B 6 C 3 F 1 mice, which is consistent with the higher levels of inflammatory cytokines observed in B 6 C 3 F 1 mice, because class switching to IgG 3 is induced by IFNγ (Snapper et al, 1992). Thus, antibody responses in both strains were enhanced by DCA treatment, but IgG subtype distribution suggested differences in cytokine-induced class switching.…”

CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo

“…However, the ability of CD4 + KJ1-26 + cells sorted from mice made tolerant to OVA with the anti-CD4/anti-CD8 mAb cocktail to deviate the OVA-specific Ig response towards OVA-specific IgG1 is consistent with the presence of IL-4 since IL-4 can promote the Ig switch to IgG1 [62]. In addition, the absence of IgG3 also suggests a role for IL-4 since IL-4 can inhibit the Ig switch to IgG3 [62,65]. These data are consistent with our previously published data that showed that CD4 + regulatory T cells induced by the anti-CD4/anti-CD8 mAb cocktail were able to inhibit transplantation rejection on transfer into new mice [48], and that this protective effect required the presence of IL-4 [48].…”

“…In light of the fact that we have shown previously that regulatory cells generated using the anti-CD4/anti-CD8 mAb cocktail inhibit transplantation rejection using an IL-4-dependent mechanism [48], we have chosen to test the ability of the transferred tolerant DO11.10 cells to exert regulatory activity by determining their ability to alter the isotype of the antibody response to OVA. Thus, IL-4 promotes the isotype switch to IgG1 [62] and IgE [63,64], whereas IFN-γ promotes the isotype switch to IgG3 [65] and IgG2a [65,66]. TGF-β promotes the switch to IgA [67], and IL-10 promotes the switch to IgG1 and IgG3 [68].…”

Expression of Natural Autoantibodies in MRL-lpr Mice Protects from Lupus Nephritis and Improves Survival

“…Because IgG3 is generally considered to be the Ab subclass in response to TI-2 Ags, it is possible that there is a dysregulation in TI-2 immune response in MRL-lpr mice and that this dysregulation can be corrected by the expression of ppc1-5 NAA. There are also reports that IgG3 production is IFN-g dependent (66,67). It is therefore possible that the expression of ppc1-5 NAA in MRL-lpr mice can downregulate IFN-g production (possibly by CD8 + T cells as shown in Fig.…”