A two‐signal model for regulation of immunoglobulin isotype switching

A characteristic feature of the humoral immune response is a switch from IgM to other Ig iso‐types that typically occurs subsequent to a first exposure to antigen, intimately, isotype switching involves a DNA rearrangement that recombines a variable region gene, initially juxtaposed to the μ constant region gene (C μ ), with a constant region gene located downstream of C μ. Isotype switching is controlled by T lymphocyte‐derived cytokines, such as interleukin‐4 (IL‐4), γ‐interferon (γ‐IFN), and TGF β , which direct B lymphocytes to switch to specific Ig classes. For example, IL‐4, directs murine B cells to produce IgG 1 and IgE, and human B cells to produce IgE and IgG 4 . IL‐4 appears to direct switching to IgE and IgG 1 by inducing transcription of the ∊ and γ1 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.— Purkerson, J.; Isakson, P. A two‐signal model for regulation of immunoglobin isotype switching. FASEB J. 6: 3245‐3252; 1992.