Immunological implications of pregnancy-induced microchimerism

Key Points The benefits of viviparity in placental mammals require dedicated immunological adaptations in mothers and offspring to avert maternal–fetal conflict during pregnancy. Given the dominant role that reproductive fitness has in driving positive refining selection, adaptations that enforce fetal tolerance and promote maternal well-being are likely to be engrained in mammalian reproduction. Expanded systemic immune tolerance occurs in mothers, and allows the widespread seeding and persistence of genetically foreign fetal microchimeric cells in maternal tissues during pregnancy and after parturition. Genetically foreign maternal cells, which express non-inherited maternal antigens, are vertically transferred into offspring during pregnancy. These maternal microchimeric cells persist throughout postnatal development into adulthood, and sustain a persistent immunological tolerance to non-inherited maternal antigens in the offspring. The bidirectional transfer of genetically foreign cells between mothers and their offspring during pregnancy is probably not accidental. Instead, microchimeric cells that express familially relevant traits are purposefully retained to promote genetic fitness by improving the outcome of future pregnancies. Expanded immune tolerance to genetically foreign antigens expressed by microchimeric cells (the 'microchiome') extends how the immunological identity of individuals is defined beyond classical models of binary 'self' versus 'non-self' antigen discrimination to include an expanded repertoire of familially relevant 'extended-self' antigens. Despite a uniform agreement on the existence of microchimeric cells, little is currently known about their cellular identity, molecular phenotype and interactions with the immune system. Further study of the effects of microchimeric cells may not only reveal new approaches for improving the outcomes of pregnancy, but also for developing innovative therapeutic solutions to other immunological problems such as autoimmunity and transplantation. This Review discusses how genetically discordant microchimeric cells transferred between a mother and her offspring during pregnancy have important implications for definitions of immunological identity and tolerance. Immunological identity is traditionally defined by genetically encoded antigens, with equal maternal and paternal contributions as a result of Mendelian inheritance. However, vertically transferred maternal cells also persist in individua