Autoreactivity in naïve human fetal B cells is associated with commensal bacteria recognition

Extensive immunoglobulin gene rearrangements allow humans to recognize a diversity of potential pathogens. This antibody repertoire is more restricted during early life to prevent the generation of autoreactive B cells, though tolerance does not appear to be complete. Chen et al. examined the reactivities of antibodies cloned from individual human fetal B cells residing in the liver, bone marrow, and spleen. They observed the accumulation of autoreactive and polyreactive B cells, which were frequently cross-reactive to commensals in the absence of any somatic hypermutation. The generation of these reactive B cells before they are ever exposed to microbes may promote later beneficial commensal- host interactions and/or augmented host defense during the first weeks of life. Science this issue p. 320 The fetal antibody repertoire binds both self and commensal bacteria. Restricted V(D)J recombination during fetal development was postulated to limit antibody repertoire breadth and prevent autoimmunity. However, newborn serum contains abundant autoantibodies, suggesting that B cell tolerance during gestation is not yet fully established. To investigate this apparent paradox, we evaluated the reactivities of more than 450 antibodies cloned from single B cells from human fetal liver, bone marrow, and spleen. We found that incomplete B cell tolerance in early human fetal life favored the accumulation of polyreactive B cells that bound both apoptotic cells and commensal bacteria from healthy adults. Thus, the restricted fetal preimmune repertoire contains potentially beneficial self-reactive innate-like B cell specificities that may facilitate the removal of apoptotic cells during development and shape gut microbiota assembly after birth.