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The addition of TGF-beta to cultures of LPS-stimulated murine B cells causes a approximately 10-fold enhancement of IgA production, yet causes a 10-fold decrease in total Ig production. IL-2 and, to a lesser extent, IL-5 synergize with TGF-beta to further enhance IgA production and partially reverse the inhibition of total Ig production. IgA constitutes only approximately 0.1% of total Ig in LPS-stimulated cultures, but that percentage rises to 15-25% in cultures to which TGF-beta and IL-2 are added. TGF-beta induces a substantial increase in IgA production from sIgA- B cells but inhibits IgA production by sIgA+ cells. This finding suggests that TGF-beta acts as an isotype-specific switch factor for IgA.

SummaryInterleukin 4 (11,4)-induced IgE production coincides with the appearance of the 2.2-kb productive e-mRNA, but is preceded by synthesis of a 1 .7-kb e-RNA. Analysis of cDNA copies of the 5' end of this RNA indicated that the 1.7-kb E-RNA is a germline e immunoglobulin heavy chain transcript with an exon mapping 5' to the switch region . Transcription through switch regions has been implicated in the control of class switching . However, IL4 or cloned CD4+ T cells were able to induce germline e transcripts without inducing IgE synthesis, for which both signals were required. These results indicate that induction of human germline e-RNA does not necessarily result in IgE synthesis, and that additional regulatory mechanisms are involved in class switching.

Although it has been established that IL-4 enhances both IgG1 and IgE secretion in LPS-stimulated B cell cultures, these studies failed to determine whether IL-4 preferentially induces isotype switching or preferentially allows for the maturation of precommitted precursor cells. To distinguish between these possibilities, it is necessary to ascertain the effect of IL-4 on the isotypes secreted by individual precursor cells during clonal expansion. Therefore, clonal cultures of B cells stimulated with a Th2 helper cell line specific for rabbit Ig and rabbit anti-mouse IgM were established. The majority of B cells are capable of undergoing clonal expansion under these conditions. To vary the level of IL-4 present, either IL-4 or anti-IL-4 was added to cultures. In the presence of IL-4 there was an increase in the proportion of clones that secreted IgE and a decrease in the proportion of clones that secreted IgM. The addition of IL-4 to cultures also increased the amount of IgE secreted by individual clones. Thus, these experiments definitively prove that IL-4 causes specific heavy chain class switching to IgE in Th2-stimulated B cell cultures. In contrast, IL-4 does not affect the proportion of clones secreting IgG1, suggesting that other consequences of Th cell-B cell interactions play a role in the generation of an IgG1 response.