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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.

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.

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Figure 1: Pregnancy imprints expanded immune tolerance in mothers and offspring.
Figure 2: Familial sources of microchimeric cells that establish the 'microchiome'.
Figure 3: Potential pathways by which maternal microchimeric cells seeded in fetal tissues may influence immune system development in offspring.

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Acknowledgements

The writing of this Review and reference to the authors' own work were made possible through funding by Cusanuswerk-Studienförderung (to I.A.S.); Deutsche Forschungsgemeinschaft (AR232/25-1 in KFO296 and AR232/27-1 to P.C.A.); the US National Institutes of Health, Office of the Director (DP1AI131080 to S.S.W.); the US National Institute of Allergy and Infectious Disease (R01AI100934 and R01AI120202 to S.S.W.); and the March of Dimes Foundation (FY15-254 to S.S.W.). S.S.W. is a Burroughs Wellcome Fund Investigator in the pathogenesis of infectious disease and is a Howard Hughes Medical Institute Faculty Scholar.

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Correspondence to Sing Sing Way.

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Supplementary information

Supplementary information S1 (table)

Cellular phenotype of maternal and fetal microchimeric cells during pregnancy and after parturition (DOC 521 kb)

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Glossary

Immunological identity

The signature of distinct protein antigens that is encoded by the unique DNA of each individual, which includes MHC haplotype alleles and other alloantigens.

Viviparity

Development of offspring inside the body of the parent that results in the birth of live offspring capable of independent existence.

Fetal tolerance

The processes that allow fetal cells and tissues that express genetically foreign paternal antigens to avoid immune rejection and coexist in harmony inside expecting mothers during pregnancy.

Microchimeric cells

Rare cells found in one individual that originate from another individual and are genetically distinct from the host individual.

Non-inherited maternal antigens

(NIMAs). The half of genetically encoded maternal antigens that are not transmitted to an offspring by classical Mendelian inheritance.

Allogeneic pregnancies

Pregnancies that occur as the result of mating between individuals that are genetically distinct. For genetically identical, inbred animal strains, this refers to matings between unique male and female strains that have discordant MHC haplotypes, a setting that recapitulates the natural diversity of MHC alleles among individuals in outbred populations.

Peripherally induced Treg cells

CD4+ T cells that are induced to express forkhead box protein P3 and acquire immunosuppressive properties by cognate antigen stimulation in extrathymic peripheral tissues.

Maternal–fetal histocompatibility

The degree of similarity between genetically encoded MHC alleles in each mother–child pair.

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Kinder, J., Stelzer, I., Arck, P. et al. Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol 17, 483–494 (2017). https://doi.org/10.1038/nri.2017.38

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