The Liaison of Isotype Class Switch and Mismatch Repair

T he Ig class switch allows the expression of a V region with new C H regions associated with various effector functions (for reviews, see references 1 and 2). Switch re-combination (SR) occurs by an intrachromosomal deletion process in which the intervening genetic material between the switch (S) regions is excised as a circle. The recombina-tion breakpoints are located within S regions but not at consensus recombination signal sequences, suggesting that SR is not site-specific recombination (3). Switch junctions do not contain long stretches of homology, arguing that homologous recombination does not contribute to this process. Thus, SR is unique in that it does not fall neatly into one of the well-defined categories of recombination. Results indicating an important role for mismatch repair (MMR) proteins in Ig class switch, published in a recent issue of EMBO (European Molecular Biology Organization) Journal (4) and in this issue of The Journal of Experimental Medicine (5), serve to significantly augment our understanding of the long-elusive molecular mechanism of Ig SR. A model for the mechanism of SR was previously proposed in which heteroduplex DNA was located at DNA ends in recombination intermediates (6). Successful completion of the switch reaction required removal of the nonhomologous ends. In a perspicacious search for activities that mediate processing of heteroduplex DNA ends in SR, Schrader et al. (5) analyzed mice deficient for the MMR proteins Msh2, Pms2, Mlh1 and the compound knockout of Pms2/Mlh1 for their ability to support isotype switching in vitro. Extensive analysis of proliferation by tri-tiated thymidine uptake and of cell cycle by propidium io-dide staining and flow cytometry demonstrated no difference between MMR-deficient and normal splenic B cells. MMR-deficient splenic B cells stimulated with LPS and the appropriate lymphokines displayed a 35–75% reduction in isotype switching to IgG3, IgG1, IgG2b, and IgA. This evaluation was based on cell surface staining for switched isotypes and was confirmed by digestion-circularization PCR. It is striking that the degree of isotype switch reduction is partial and somewhat variable among the isotypes. In a screen for the effects of the MMR protein Msh2 on somatic hypermutation, it was noted that mice deficient in Msh2 could make good IgM but poor IgG responses to T cell–dependent antigen, suggesting that SR might be selectively affected (7). Ehrenstein and Neuberger (4) have now systematically examined this issue in Msh2-deficient mice to find that in both the antigen-specific T cell–dependent response to …