IFN-<sup>γ</sup>is a potent inducer of Ig secretion by sort-purified murine B cella activated through the mlg, but not the CD40,signaling pathway

IgG2a, with γ2a H chains, is important for protection against viruses and other intracellular pathogens. Although a large portion of IgG2a expression is dependent upon IFN-γ, some germline transcription and switch recombination to the murine γ2a H chain gene expression are independent of IFN-γ. We found that agonistic anti-CD40 Abs injected into IFN-γ-deficient mice induce a >200-fold increase in the amount of serum Ig2a, while other Ig isotypes are increased by 16-fold or less. In vitro, ligation of CD40 on B cells, without the addition of other B cell activators or cytokines, results in germline transcription and switch recombination that are largely restricted to the γ2a gene. These results suggest that some immune responses to infectious agents can result in large amounts of IgG2a expression through ligation of CD40, without the expression of IFN-γ by Th1 or other cells.

Section: Discussionmentioning

confidence: 92%

Induced Expression of Murine γ2a by CD40 Ligation Independently of IFN-γ

Collins

Shi

Burrell

et al. 2006

“…Previous reports have demonstrated that B cells stimulated via CD40 were extremely sensitive to Fas-mediated apoptosis, whereas dual ligation of CD40 and surface Ag receptors made them resistant (50,51). In B cells activated through LPS or CD40 stimulation, IFN-␥ inhibits Ab secretion in the absence of surface Ig stimulation, but induces Ab secretion in the presence of surface Ig stimulation (52)(53)(54)(55). These previous data are consistent with our current findings, in that neutralization of IFN-␥ activity as well as blockade of B cell apoptosis are required to increase IgM production in cultures with high dose Ag (Fig.…”

Section: Discussionmentioning

confidence: 99%

Naive CD4+ T Cells Exhibit Distinct Expression Patterns of Cytokines and Cell Surface Molecules on Their Primary Responses to Varying Doses of Antigen

Ise

Totsuka

Sogawa

et al. 2002

The amount of an Ag used for stimulation affects the type and magnitude of T cell responses. In this study we have investigated the primary response of naive CD4+ T cells derived from OVA-specific TCR-transgenic mice (OVA23-3) upon stimulation with varying doses of the antigenic peptide, OVA323–339. IL-4 expression was maximal with 50 nM Ag and decreased significantly with increasing doses. In contrast, IFN-γ expression, which was also detected at 50 nM Ag, increased with increasing doses. The expression patterns of mRNA for the Th2-specific transcription factors GATA-3 and c-Maf were parallel to that of IL-4. These expression profiles were not altered by the addition of anti-IL-4 plus anti-IL-12 mAbs, suggesting that cytokine receptor signaling is not essential. Naive CD4+ T cells stimulated with 5 nM Ag elicited IgM secretion from cocultured B cells, whereas those stimulated with 50 nM Ag or more elicited apoptosis of B cells. This may be because at lower doses of Ag (5 nM), naive CD4+ T cells express CD40 ligand and OX40, whereas at higher doses (50 nM), they express Fas ligand. Clearly, the expression of each type of molecule depends on the Ag dose, and different molecules had different expression patterns. Thus, in the primary response, naive CD4+ T cells can exhibit different functions depending on the dose of Ag.

“…IL-6 is well recognized as a factor acting on B cells to induce Ig secretion (44), and the production of IL-6 by B cells infected in vitro with ␥HV68 (43) suggests a role for the cytokine as a virus-induced autocrine growth factor. IFN-␥ induces Ig production by activated B cells (45) and is also the major cytokine promoting class switching to IgG2a (46). These functions suggest a significant role for IFN-␥ in the vigorous, IgG2a-biased, nonspecific Ab response associated with ␥HV68 infection.…”

Section: Nonspecific Ab Production In Cytokine-deficient Micementioning

confidence: 94%

Analysis of the Virus-Specific and Nonspecific B Cell Response to a Persistent B-Lymphotropic Gammaherpesvirus

Sangster

Topham

D’Costa

et al. 2000

111

117

Respiratory challenge of mice with murine gammaherpesvirus 68 (γHV68) results in acute replication in respiratory epithelial cells and persistent, latent infection of B cells and macrophages. γHV68 elicits virus-specific Ab, and also nonspecifically activates B cells to Ab production through a CD4+ T cell-dependent process. The current analysis characterizes virus-specific and nonspecific Ab production at the single cell level and investigates the requirements and nature of the nonspecific response. Virus-specific Ab-forming cell (AFC) numbers were dwarfed by the increase in total AFC in all sites examined, indicating substantial nonspecific Ab production. Clear increases and decreases in specific and total AFC numbers occurred in the lymph nodes draining the respiratory tract and the spleen, but AFC numbers in the bone marrow (BM) increased to a plateau and remained constant. The longevity of the BM response was reflected in a sustained increase in virus-specific and total serum Ab levels. Generally, the IgG2a and IgG2b isotypes predominated. Analysis of cytokine-deficient mice, CD40 ligand-deficient mice, and radiation BM chimeras lacking MHC class II expression specifically on B cells indicated that nonspecific Ab production is independent of IL-6 or IFN-γ, and dependent on cognate CD4+ T cell help. Several observations were consistent with polyclonal B cell activation by γHV68, including the induction of durable serum levels of IgG reactive with mammalian dsDNA and murine type II collagen. Our findings indicate new directions for studies of this valuable model of γ-herpesvirus pathogenesis.