AID overwhelms Polβ in class-switching B cells

The immune system takes its cues from antigen-presenting cells (APCs) to either go on the offensive against a foreign enemy or to stand down and tolerate a harmless threat. Ehirchiou et al. (page 1519) now report a new mechanism by which APCs power down the immune system: an APC surface receptor suppresses the development of overzealous T helper (Th)-17 cells. According to dogma, APCs that have only few costimulatory receptors dampen immunity. These APCs can't give T cells the stimulatory boost they need to become offensive. But some APCs with lots of costimulatory receptors can somehow still keep T cells in low gear. One APC receptor that might direct this alternative pathway, the authors hypothesized, is CD11b. Mice need this integrin to remove neutrophils and macrophages from infection sites and subdue inflammation. CD11b deficiency also worsens autoimmunity, suggesting that the receptor might enable the immune system to tolerate certain antigens. The authors studied the effect of CD11b on tolerance by feeding normal and CD11b-deficient mice low doses of ovalbumin (OVA) for a week and then challenging them with high doses of this antigen. The CD11b-deficient mice failed this tolerance test and generated high levels of OVA-specific T cells. Tolerance was restored, however, when these mice were supplied with APCs from normal mice. The CD11b-deficient mice had high levels of two cytokines, IL-6 and IL-23, which support the growth of Th17 cells, a T cell subset that is associated with allergies and autoimmunity. The mutant mice had almost three times the normal numbers of Th17 cells, suggesting that CD11b suppresses the growth of this dangerous T cell subset and thereby establishes tolerance. The authors are now investigating whether CD11b signaling directly blocks IL-6/IL-23 production and whether a particular APC subset requires CD11b expression to prevent the development of Th17 cells. TH17 cells thrive and react to the OVA antigen in mice lacking CD11b. The machinery that repairs spontaneous DNA mutations fails when the mutations are purposely induced by an enzyme in activated B cells. Wu and Stavnezer (page 1677) now find that the enzyme wins because it induces too much damage for repair proteins to keep up with. The spontaneous mutation of cytosine bases to uracils is corrected by a process that removes the wrong bases, cuts the DNA at the empty spots, and reinserts the correct bases. This normally efficient process fails in B cells that are switching from producing …