A 2-SIGNAL MODEL FOR REGULATION OF IMMUNOGLOBULIN ISOTYPE SWITCHING

A characteristic feature of the humoral immune response is a switch from IgM to other Ig isotypes that typically occurs subsequent to a first exposure to antigen. Ultimately, isotype switching involves a DNA rearrangement that recombines a variable region gene, initially juxtaposed to the mu constant region gene (Cmu), with a constant region gene located downstream of Cmu. Isotype switching is controlled by T lymphocyte-derived cytokines, such as interleukin-4 (IL-4), gamma-interferon (gamma-IFN), and TGFbeta, which direct B lymphocytes to switch to specific Ig classes. For example, IL-4, directs murine B cells to produce IgG1 and IgE, and human B cells to produce IgE and IgG4. IL-4 appears to direct switching to IgE and IgG1 by inducing transcription of the epsilon and gamma1 constant region genes before switch recombination. However, IL-4 is not a sufficient stimulus for isotype switching, and additional signals are required to complete this process. This second signal can be provided by physical contact with activated T cells, which may involve, at least in part, ligation of the CD40 molecule. For murine B cells the second signal may also be provided by IL-5. Isotype switching in B lymphocytes may provide a useful model for directed DNA recombination in higher eukaryotes.