Immunological implications of pregnancy-induced microchimerism

Abstract

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 individuals at very low levels throughout postnatal development. Reciprocally, mothers are seeded during pregnancy with genetically foreign fetal cells that persist long after parturition. Recent findings suggest that these microchimeric cells expressing non-inherited, familially relevant antigenic traits are not accidental 'souvenirs' of pregnancy, but are purposefully retained within mothers and their offspring to promote genetic fitness by improving the outcome of future pregnancies. In this Review, we discuss the immunological implications, benefits and potential consequences of individuals being constitutively chimeric with a biologically active 'microchiome' of genetically foreign cells.

Fig. 1. Pregnancy imprints expanded immune tolerance in mothers and offspring

(a) Among the universe of all possible antigens to which the immune system can theoretically respond, immune tolerance expands in mothers during pregnancy beyond her own genetically encoded self-antigens (orange), to encompass genetically foreign paternal antigens expressed by the developing fetus (blue). This coincides with the widespread seeding of maternal tissues by genetically foreign fetal cells during pregnancy. Long-term persistence of these fetal cells after parturition suggests that expanded tolerance is maintained in mothers to include fetal antigens from prior pregnancy. (b) Immune tolerance expands in offspring beyond genetically encoded self-antigens (blue), to also include genetically foreign non-inherited maternal antigens (NIMAs) (orange). This begins with the vertical transfer of maternal cells into offspring during in utero development. The long-term postnatal retention of these genetically foreign maternal cells in the tissue of offspring is indicative of persistently expanded tolerance to NIMAs. (c) Immune tolerance further expands during next-generation pregnancies in female offspring beyond her own genetically encoded self-antigens (blue) and noninherited antigens from her own mother (orange), to include genetically foreign paternal antigens expressed by the developing fetus (green).

Fig. 2. Familial sources of microchimeric cells that establish the ‘microchiome’

The bidirectional transfer of genetically foreign cells between a mother and her fetus results in fetal microchimerism (FMC) in the mother (orange arrow) and maternal microchimerism (MMC) in the offspring (brown arrow). In addition to vertical transfer of maternal cells to next-generation (filial) offspring, it is also possible that cross-generational transfer of microchimeric cells from the maternal grandmother may occur (dashed brown and dashed dark blue arrows). As mothers receive genetically distinct fetal microchimeric cell populations in each successive pregnancy, microchimeric cells from older siblings may also be transferred into younger siblings (pink arrow). This exchange of genetically foreign cells may also occur in utero between dizygotic twins (yellow and light blue arrows). Thus, females are the primary reservoirs for transferring microchimeric cells between past and future generations, and the diversity of microchimeric cells in each individual, or their ‘microchiome’, is likely further influenced by birth order and parity.

Fig. 3. Potential pathways by which maternal microchimeric cells seeded in fetal tissues may influence immune system development in offspring

Several primary and secondary lymphoid tissues (thymus, blood, lymph node and bone marrow) are seeded by genetically foreign maternal microchimeric cells during gestation^,. This seeding coincides with important milestones in the development of fetal and neonatal haematopoietic cells including the development of central tolerance, and differentiation of regulatory T (T_reg) cells in the thymus (tT_reg cells) and periphery (pT_reg cells)^,,. Evolutionary adaptations including the emergence of immunosuppressive CD71⁺ erythroid cells and diminished responsiveness of neonatal immune cells favour the development of immune tolerance in early postnatal development to avert pathological inflammation driven by commensal microbial colonization. Given the near ubiquitous presence of maternal cells in these developing fetal tissues, and the profound short and long-term implications of impaired or delayed fetal–neonatal immune ontogeny, important areas for future investigation include how maternal microchimeric cells may affect functional hematopoiesis in offspring.