The selection of the particular C region for class switch recombination is not random but is regulated by the cytokines produced by TFH cells and other cells during the immune response. Different cytokines preferentially induce switching to different isotypes (Fig. 10.23). Cytokines induce class switching in part by inducing the production of RNA transcripts through the switch regions that lie 5ʹ to each heavy-chain C gene segment. When activated B cells are exposed to IL-4, for example, transcription from promoters that lie upstream of the switch regions of Cγ1 and Cε can be detected a day or two before switching occurs. This will make it possible for switch to occur to either of these two heavy-chain C genes, but in any particular germinal center B cell, recombination will occur in only one. In the example of class switching shown in Fig. 10.21, transcription through the Sε regions caused the rearrangement between the Sμ and Sε regions, making the IgE isotype antibody. This results because IL-4 signaling activates the transcription factor STAT6, which initiates transcription of the Iε promoter upstream of the Sε region. Other cytokines activate other promoters upstream of other switch regions to produce other antibody classes. TFH cells also produce IL-21, which promotes switching to IgG1 and IgG3. Transforming growth factor (TGF)-β induces switching to IgG2b (Cγ2b) and IgA (Cα). IL-5 promotes switching to IgA, and interferon (IFN)-γ induces switching to IgG2a and IgG3.
The individual cytokines induce (violet) or inhibit (red) the production of certain antibody classes. Much of the inhibitory effect is probably the result of directed switching to a different class. The actions of IL-21 on class switching are regulated by IL-4. These data are drawn from experiments with mouse cells.
Fig. 10.23 Different cytokines induce switching to different antibody classes.
InducesInhibitsInhibits Induces Induces InducesInduces Induces Induces Induces Induces Inhibits Inhibits Inhibits Inhibits Inhibits Inhibits IgEIgG2aIgG3IgM IgG1 IgG2b IgACytokines IL-4 IL-5 IFN-˜TGF-°Role of cytokines in regulating expression of antibody classes Augments production IL-21 10-13 B cells that survive the germinal center reaction eventually differentiate into either plasma cells or memory cells.
When B cells have undergone affinity maturation and class switching, some eventually exit from the light zone and start to differentiate into plasma cells that produce large amounts of antibody. In B cells, the transcription factors Pax5 and Bcl-6 inhibit the expression of transcription factors required for plasma-cell differentiation, and both Pax5 and Bcl-6 are downregulated when the B cell starts differentiating. The transcription factor IRF4 then induces the expression of BLIMP-1, a transcriptional repressor that switches off genes required for B-cell proliferation, class switching, and affinity maturation. B cells in which BLIMP-1 is induced become plasma cells; they cease proliferating, increase the synthesis and secretion of immunoglobulins, and change their cell-surface properties. Plasma cells downregulate CXCR5 and upregulate CXCR4 and α4:β1 integrins so that they can leave the germinal centers and home to peripheral tissues.