MISMATCH REPAIR DEFICIENCY INTERFERES WITH THE ACCUMULATION OF MUTATIONS IN CHRONICALLY STIMULATED B-CELLS AND NOT WITH THE HYPERMUTATION PROCESS

Primary responses to the hapten phenyloxazolone and chronic responses to environmental antigens occuring in Peyer's patches were analyzed in two different mismatch repair-deficient backgrounds. Paradoxically, w hereas primary responses were found normal in MSH2- and only slightly diminished in PMS2-deficient mice, mutations in Peyer's patch B cells from both k.o. animals were reduced three times, the subset of Peyer's patch B cells with highly mutated sequences being specifically missin g in the mismatch repair-deficient context. Strikingly, germinal cente r B cells from Peyer's patches of k.o. animals showed microsatellite i nstability at an unprecedented level. We thus propose that the amount of DNA damages generated prevents these cells from recycling in germin al centers and that mismatch repair deficiency is only the indirect ca use of the lower mutation incidence observed.