Gamma interferon (IFN-gamma) and B cell stimulatory factor-1 (BSF-1), also known as interleukin-4, are T cell-derived lymphokines that have potent effects on B cell proliferation and differentiation. They are often secreted by distinct T cell clones. It is now shown that IFN-gamma stimulates the expression of immunoglobulin (Ig) of the IgG2a isotype and inhibits the production of IgG3, IgG1, IgG2b, and IgE. By contrast, BSF-1 has powerful effects in promoting switching to the expression of IgG1 and IgE but markedly inhibits IgM, IgG3, IgG2a, and IgG2b. These results indicate that BSF-1 and IFN-gamma as well as the T cells that produce them may act as reciprocal regulatory agents in the determination of Ig isotype responses. The effects of IFN-gamma and BSF-1 on isotype expression are independent.

In this review we have attempted to define the characteristics of TI-2 antigens that enable them to stimulate antibody production in the absence of T cell help. One of the most critical properties of this group of antigens is their ability to deliver prolonged and persistent signaling to the B cell. This by itself is not however sufficient to stimulate Ig synthesis, and they must therefore stimulate non-T cells to interact with the B cells either directly or indirectly via cytokine production. There is evidence implicating the NK cell and T cell as playing this important role in response to TI antigens. Furthermore, we discuss the importance of cytokines such as IL-3, GMCSF, and IFN-gamma, which significantly enhance antibody production by these antigens. Finally, we present evidence demonstrating that B cell activation via TI stimuli does not play merely a permissive role in allowing for cell cycle entry and enhanced responsiveness to other stimuli. Rather, the nature of the B cell activating signal is critical in determining the quantitative and qualitative profile of Ig isotype production.

The nfkb2 gene is a member of the Rel/NF-κB family of transcription factors. COOH-terminal deletions and rearrangements of this gene have been associated with the development of human cutaneous T cell lymphomas, chronic lymphocytic leukemias, and multiple myelomas. To further investigate the function of NF-κB2, we have generated mutant mice carrying a germline mutation of the nfkb2 gene by homologous recombination. NF-κB2–deficient mice showed a marked reduction in the B cell compartment in spleen, bone marrow, and lymph nodes. Moreover, spleen and lymph nodes of mutant mice presented an altered architecture, characterized by diffuse, irregular B cell areas and the absence of discrete perifollicular marginal and mantle zones; the formation of secondary germinal centers in spleen was also impaired. Proliferation of NF-κB2–deficient B cells was moderately reduced in response to lipopolysaccharide, anti-IgD-dextran, and CD40, but maturation and immunoglobulin switching were normal. However, nfkb2 (−/−) animals presented a deficient immunological response to T cell–dependent and –independent antigens. These findings indicate an important role of NF-κB2 in the maintenance of the peripheral B cell population, humoral responses, and normal spleen architecture.

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IL-4/B cell stimulatory factor-1 is a T cell-derived lymphokine that has been shown to enhance IgG1 and IgE and to suppress IgG3 and IgG2b secretion by B cells stimulated with bacterial LPS. We show here that the stimulation of IgG1 and IgE secretion in response to rIL-4 is differentially regulated. The dose-response curve for IgG1 production is bimodal with peaks at 100 and 10,000 U/ml. IgE production is modest at 100 U/ml and exhibits a progressive enhancement as the IL-4 concentration is increased to 10,000 U/ml, reaching approximately 1 microgram of IgE from an initial cell number of 2 X 10(4). Both of these effects are reversed by monoclonal anti-IL-4 antibody. Neither the enhancing nor suppressing effects of IL-4 can be explained by changes in viable cell yields or [3H]thymidine incorporation. The production of both IgG1 and IgE is controlled by IL-4 in a two-phase manner. During the initial 2 d of culture with LPS, IL-4 action for both IgG1 and IgE production is relatively concentration independent at doses greater than 600 U/ml. This 2-d treatment leads to maximal IgG1 production at day 6 with no further addition of IL-4. Addition of IL-4 during the final 4 d of culture has no effect at concentrations under 100 U/ml. At higher concentrations, IL-4 is strikingly suppressive for IgG1 production. By contrast, little IgE is produced unless IL-4 is present after 2 d of culture and the response is directly dependent on the concentration of IL-4 during this second phase of culture with maximal responses observed at 10,000 U/ml. These differences in IL-4 requirements for IgG1 and IgE production, respectively, may have an important role in the regulation of the synthesis of these isotypes in responses to microbial antigens.

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.

species encoded by different C H genes in the germline (Stavnezer-Nordgren and Sirlin, 1986; Yancopoulos et and Piotr Zelazowski* *Department of Pathology al., 1986). Germline C H RNAs are spliced products of distinct I exons, located 5Ј to every S region, and the The Uniformed Services University of the Health Sciences immediate 3Ј C H gene (Figure 1). Transcription initiates within a promoter 5Ј to the I exon, proceeds through Bethesda, Maryland 20814 † Department of Biochemistry and Cell Biology the S region, and terminates at the 3Ј end of the C H gene.