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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Medzhitov, R. & Janeway, C. A. Jr. How does the immune system distinguish self from nonself? Semin. Immunol. 12, 185–188 (2000).
Paul, W. E. Self/nonself-immune recognition and signaling: a new journal tackles a problem at the center of immunological science. Self Nonself 1, 2–3 (2010).
Owen, R. D. Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102, 400–401 (1945). This study provides a pioneering description of expanded immune tolerance primed by early developmental exposure to genetically foreign antigens.
Medawar, P. B. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7, 320–338 (1953).
Erlebacher, A. Mechanisms of T cell tolerance towards the allogeneic fetus. Nat. Rev. Immunol. 13, 23–33 (2013).
Erlebacher, A. Immunology of the maternal–fetal interface. Annu. Rev. Immunol. 31, 387–411 (2013).
Robertson, S. A., Petroff, M. G. & Hunt, J. in Physiology of Reproduction Ch. 41 (eds Plant, T. M. & Zeleznik, A. J.) 1835–1874 (Academic Press, 2015).
Arck, P. C. & Hecher, K. Fetomaternal immune cross-talk and its consequences for maternal and offspring's health. Nat. Med. 19, 548–556 (2013).
Rijnink, E. C. et al. Tissue microchimerism is increased during pregnancy: a human autopsy study. Mol. Hum. Reprod. 21, 857–864 (2015).
Khosrotehrani, K., Johnson, K. L., Guegan, S., Stroh, H. & Bianchi, D. W. Natural history of fetal cell microchimerism during and following murine pregnancy. J. Reprod. Immunol. 66, 1–12 (2005).
Jonsson, A. M., Uzunel, M., Gotherstrom, C., Papadogiannakis, N. & Westgren, M. Maternal microchimerism in human fetal tissues. Am. J. Obstet. Gynecol. 198, 325.e1–325.e6 (2008).
Mold, J. E. et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 322, 1562–1565 (2008). This study provides evidence that fetal effector T cells are capable of alloreactivity, but are actively suppressed by fetal immune-suppressive T reg cells.
Bianchi, D., Zickwolf, G., Weil, G., Sylvester, S. & DeMaria, M. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc. Natl Acad. Sci. USA 93, 705–708 (1996). This study definitively demonstrates that genetically foreign male cells of presumed fetal origin can persist in mothers decades after parturition.
Maloney, S. et al. Microchimerism of maternal origin persists into adult life. J. Clin. Invest. 104, 41–47 (1999). This study definitively demonstrates that maternal microchimeric cells persist in healthy offspring.
Kinder, J. M. et al. Cross-generational reproductive fitness enforced by microchimeric maternal cells. Cell 162, 505–515 (2015). This study establishes the cross-generational reproductive benefits of maternal microchimeric cells retained in offspring by using tools for the selective in vivo depletion of these cells.
Confavreux, C., Hutchinson, M., Hours, M. M., Cortinovis-Tourniaire, P. & Moreau, T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N. Engl. J. Med. 339, 285–291 (1998).
Ostensen, M. & Villiger, P. M. The remission of rheumatoid arthritis during pregnancy. Semin. Immunopathol. 29, 185–191 (2007).
Bischoff, A. L. et al. Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial. PLoS ONE 8, e56700 (2013).
Schlaudecker, E. P., McNeal, M. M., Dodd, C. N., Ranz, J. B. & Steinhoff, M. C. Pregnancy modifies the antibody response to trivalent influenza immunization. J. Infect. Dis. 206, 1670–1673 (2012).
Herzenberg, L. A., Bianchi, D. W., Schroder, J., Cann, H. M. & Iverson, G. M. Fetal cells in the blood of pregnant women: detection and enrichment by fluorescence-activated cell sorting. Proc. Natl Acad. Sci. USA 76, 1453–1455 (1979).
Ariga, H. et al. Kinetics of fetal cellular and cell-free DNA in the maternal circulation during and after pregnancy: implications for noninvasive prenatal diagnosis. Transfusion 41, 1524–1530 (2001).
Krabchi, K. et al. Quantification of all fetal nucleated cells in maternal blood between the 18th and 22nd weeks of pregnancy using molecular cytogenetic techniques. Clin. Genet. 60, 145–150 (2001).
Gammill, H. & Nelson, J. Naturally acquired microchimerism. Int. J. Dev. Biol. 54, 531–543 (2010).
Jimenez, D. F., Leapley, A. C., Lee, C. I., Ultsch, M. N. & Tarantal, A. F. Fetal CD34+ cells in the maternal circulation and long-term microchimerism in rhesus monkeys (Macaca mulatta). Transplantation 79, 142–146 (2005).
Fujiki, Y., Johnson, K. L., Tighiouart, H., Peter, I. & Bianchi, D. W. Fetomaternal trafficking in the mouse increases as delivery approaches and is highest in the maternal lung. Biol. Reprod. 79, 841–848 (2008).
Jiang, T. T. et al. Regulatory T cells: new keys for further unlocking the enigma of fetal tolerance and pregnancy complications. J. Immunol. 192, 4949–4956 (2014).
Aluvihare, V., Kallikourdis, M. & Betz, A. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5, 266–271 (2004).
Rowe, J. H., Ertelt, J. M., Aguilera, M. N., Farrar, M. A. & Way, S. S. Foxp3+ regulatory T cell expansion required for sustaining pregnancy compromises host defense against prenatal bacterial pathogens. Cell Host Microbe 10, 54–64 (2011).
Bonney, E. A. & Brown, S. A. To drive or be driven: the path of a mouse model of recurrent pregnancy loss. Reproduction 147, R153–R167 (2014).
Rowe, J. H., Ertelt, J. M., Xin, L. & Way, S. S. Listeria monocytogenes cytoplasmic entry induces fetal wastage by disrupting maternal FoxP3+ regulatory cell-sustained fetal tolerance. PLoS Pathog. 8, e1002873 (2012).
Zenclussen, A. C. et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am. J. Pathol. 166, 811–822 (2005).
Kahn, D. & Baltimore, D. Pregnancy induces a fetal antigen-specific maternal T regulatory cell response that contributes to tolerance. Proc. Natl Acad. Sci. USA 107, 9299–9304 (2010).
Chen, T. et al. Self-specific memory regulatory T cells protect embryos at implantation in mice. J. Immunol. 191, 2273–2281 (2013).
Feuerer, M. et al. Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes. Proc. Natl Acad. Sci. USA 104, 18181–18186 (2007).
Kuswanto, W. et al. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity 44, 355–367 (2016).
Rowe, J. H., Ertelt, J. M., Xin, L. & Way, S. S. Pregnancy imprints regulatory memory that sustains anergy to fetal antigen. Nature 490, 102–106 (2012).
Erlebacher, A., Vencato, D., Price, K., Zhang, D. & Glimcher, L. Constraints in antigen presentation severely restrict T cell recognition of allogeneic fetus. J. Clin. Invest. 117, 1399–1411 (2007).
Chaturvedi, V. et al. CXCR3 blockade protects against Listeria monocytogenes infection-induced fetal wastage. J. Clin. Invest. 125, 1713–1725 (2015).
Nancy, P. et al. Chemokine gene silencing in decidual stromal cells limits T cell access to maternal–fetal interface. Science 336, 1317–1321 (2012).
Xin, L. et al. Cutting edge: committed Th1 CD4+ T cell differentiation blocks pregnancy-induced Foxp3 expression with antigen-specific fetal loss. J. Immunol. 192, 2970–2974 (2014).
Samstein, R. M., Josefowicz, S. Z., Arvey, A., Treuting, P. M. & Rudensky, A. Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal–fetal conflict. Cell 150, 29–38 (2012).
Mold, J. E. & McCune, J. M. Immunological tolerance during fetal development: from mouse to man. Adv. Immunol. 115, 73–111 (2012).
Hall, J. M. et al. Detection of maternal cells in human umbilical cord blood using fluorescence in situ hybridization. Blood 86, 2829–2832 (1995).
Stevens, A. M., Hermes, H. M., Kiefer, M. M., Rutledge, J. C. & Nelson, J. L. Chimeric maternal cells with tissue-specific antigen expression and morphology are common in infant tissues. Pediatr. Dev. Pathol. 12, 337–346 (2009).
Haynes, B. F. Phenotypic characterization and ontogeny of components of the human thymic microenvironment. Clin. Res. 32, 500–507 (1984).
Andrassy, J. et al. Tolerance to noninherited maternal MHC antigens in mice. J. Immunol. 171, 5554–5561 (2003).
Bakkour, S. et al. Analysis of maternal microchimerism in rhesus monkeys (Macaca mulatta) using real-time quantitative PCR amplification of MHC polymorphisms. Chimerism 5, 6–15 (2014).
Marleau, A. M., Greenwood, J. D., Wei, Q., Singh, B. & Croy, B. A. Chimerism of murine fetal bone marrow by maternal cells occurs in late gestation and persists into adulthood. Lab. Invest. 83, 673–681 (2003).
Piotrowski, P. & Croy, B. A. Maternal cells are widely distributed in murine fetuses in utero. Biol. Reprod. 54, 1103–1110 (1996). This study reports a pioneering immunohistochemical analysis that shows the presence and widespread distribution of maternal microchimeric cells in fetal tissues.
Owen, R. D., Wood, H. R., Foord, A. G., Sturgeon, P. & Baldwin, L. G. Evidence for actively acquired tolerance to Rh antigens. Proc. Natl Acad. Sci. USA 40, 420–424 (1954). This classical study shows that developmental exposure to genetically foreign maternal antigens confers long-lasting tolerance through reduced sensitization to the erythrocyte Rh antigen.
Claas, F. H., Gijbels, Y., van der Velden- de Munck, J. & van Rood, J. J. Induction of B cell unresponsiveness to noninherited maternal HLA antigens during fetal life. Science 241, 1815–1817 (1988). This study shows that developmental exposure to genetically foreign non-inherited maternal HLA confers long-lasting functional tolerance in humans, as indicated by the diminished priming of HLA-specific antibodies.
Burlingham, W. J. et al. The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors. N. Engl. J. Med. 339, 1657–1664 (1998). This study shows that developmental exposure to genetically foreign non-inherited maternal HLA confers long-lasting functional tolerance in humans, as indicated by prolonged renal allograft survival.
Ichinohe, T. et al. Feasibility of HLA-haploidentical hematopoietic stem cell transplantation between noninherited maternal antigen (NIMA)-mismatched family members linked with long-term fetomaternal microchimerism. Blood 104, 3821–3828 (2004).
van Rood, J. J. et al. Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or an HLA-haploidentical sibling. Blood 99, 1572–1577 (2002). This study shows that developmental exposure to genetically foreign non-inherited maternal HLA confers long-lasting functional tolerance in humans, as indicated by diminished rates of severe GVHD.
Matsuoka, K. et al. Fetal tolerance to maternal antigens improves the outcome of allogeneic bone marrow transplantation by a CD4+ CD25+ T-cell-dependent mechanism. Blood 107, 404–409 (2006).
Campbell, D. A. Jr et al. Breast feeding and maternal-donor renal allografts. Possibly the original donor-specific transfusion. Transplantation 37, 340–344 (1984).
Molitor, M. L., Haynes, L. D., Jankowska-Gan, E., Mulder, A. & Burlingham, W. J. HLA class I noninherited maternal antigens in cord blood and breast milk. Hum. Immunol. 65, 231–239 (2004).
Zhou, L. et al. Two independent pathways of maternal cell transmission to offspring: through placenta during pregnancy and by breast-feeding after birth. Immunology 101, 570–580 (2000).
Dutta, P. et al. Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice. Blood 114, 3578–3587 (2009). This study shows that maternal microchimeric cells are widely distributed in the tissues of adult offspring, and that exposure to NIMAs during lactation is essential for persisting tolerance to maternal alloantigens.
Stelzer, I. A., Thiele, K. & Solano, M. E. Maternal microchimerism: lessons learned from murine models. J. Reprod. Immunol. 108, 12–25 (2015).
Molitor-Dart, M. L. et al. Developmental exposure to noninherited maternal antigens induces CD4+ T regulatory cells: relevance to mechanism of heart allograft tolerance. J. Immunol. 179, 6749–6761 (2007).
Eikmans, M. et al. Naturally acquired microchimerism: implications for transplantation outcome and novel methodologies for detection. Chimerism 5, 24–39 (2014).
Nelson, J. L. The otherness of self: microchimerism in health and disease. Trends Immunol. 33, 421–427 (2012).
Axiak-Bechtel, S. M., Kumar, S. R., Hansen, S. A. & Bryan, J. N. Y-Chromosome DNA is present in the blood of female dogs suggesting the presence of fetal microchimerism. PLoS ONE 8, e68114 (2013).
Campbell, D., MacGillivray, I. & Carr-Hill, R. Pre-eclampsia in second pregnancy. Br. J. Obstet. Gynaecol. 92, 131–140 (1985).
Li, D. K. & Wi, S. Changing paternity and the risk of preeclampsia/eclampsia in the subsequent pregnancy. Am. J. Epidemiol. 151, 57–62 (2000).
Boddy, A. M., Fortunato, A., Wilson Sayres, M. & Aktipis, A. Fetal microchimerism and maternal health: a review and evolutionary analysis of cooperation and conflict beyond the womb. Bioessays 37, 1106–1118 (2015).
Haig, D. Does microchimerism mediate kin conflicts? Chimerism 5, 53–55 (2014).
Skjaerven, R., Wilcox, A. J. & Lie, R. T. The interval between pregnancies and the risk of preeclampsia. N. Engl. J. Med. 346, 33–38 (2002).
Tandberg, A., Klungsoyr, K., Romundstad, L. B. & Skjaerven, R. Pre-eclampsia and assisted reproductive technologies: consequences of advanced maternal age, interbirth intervals, new partner and smoking habits. BJOG 122, 915–922 (2015).
Masson, E. et al. Incidence and risk factors of anti-HLA immunization after pregnancy. Hum. Immunol. 74, 946–951 (2013).
Vilches, M. & Nieto, A. Analysis of pregnancy-induced anti-HLA antibodies using Luminex platform. Transplant. Proc. 47, 2608–2610 (2015).
Lynch, R. J. & Platt, J. L. Accommodation in organ transplantation. Curr. Opin. Organ. Transplant. 13, 165–170 (2008).
Morris, P. J. Suppression of rejection of organ allografts by alloantibody. Immunol. Rev. 49, 93–125 (1980).
Maynard, C. L., Elson, C. O., Hatton, R. D. & Weaver, C. T. Reciprocal interactions of the intestinal microbiota and immune system. Nature 489, 231–241 (2012).
Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).
Gammill, H. S., Guthrie, K. A., Aydelotte, T. M., Adams Waldorf, K. M. & Nelson, J. L. Effect of parity on fetal and maternal microchimerism: interaction of grafts within a host? Blood 116, 2706–2712 (2010).
Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).
Muller, A. C. et al. Microchimerism of male origin in a cohort of Danish girls. Chimerism 6, 65–71 (2015).
Bucher, C. et al. Role of primacy of birth in HLA-identical sibling transplantation. Blood 110, 468–469 (2007).
Dobbelstein, C. et al. Birth order and transplantation outcome in HLA-identical sibling stem cell transplantation: an analysis on behalf of the Center for International Blood and Marrow Transplantation. Biol. Blood Marrow Transplant. 19, 741–745 (2013).
Gratwohl, A. et al. Birth order and outcome after HLA-identical sibling donor transplantation. Blood 114, 5569–5570 (2009).
Mancusi, A. et al. Haploidentical hematopoietic transplantation from KIR ligand-mismatched donors with activating KIRs reduces nonrelapse mortality. Blood 125, 3173–3182 (2015).
Spalding, K. L., Bhardwaj, R. D., Buchholz, B. A., Druid, H. & Frisen, J. Retrospective birth dating of cells in humans. Cell 122, 133–143 (2005).
Nelson, J. L. et al. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351, 559–562 (1998).
Lambert, N. C. et al. Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity. J. Immunol. 164, 5545–5548 (2000).
Ponsonby, A. L. et al. Offspring number, pregnancy, and risk of a first clinical demyelinating event: the AusImmune Study. Neurology 78, 867–874 (2012).
Guthrie, K. A., Dugowson, C. E., Voigt, L. F., Koepsell, T. D. & Nelson, J. L. Does pregnancy provide vaccine-like protection against rheumatoid arthritis? Arthritis Rheum. 62, 1842–1848 (2010).
Hazes, J. M., Dijkmans, B. A., Vandenbroucke, J. P., de Vries, R. R. & Cats, A. Pregnancy and the risk of developing rheumatoid arthritis. Arthritis Rheum. 33, 1770–1775 (1990).
Lambe, M., Bjornadal, L., Neregard, P., Nyren, O. & Cooper, G. S. Childbearing and the risk of scleroderma: a population-based study in Sweden. Am. J. Epidemiol. 159, 162–166 (2004).
Masera, S. et al. Parity is associated with a longer time to reach irreversible disability milestones in women with multiple sclerosis. Mult. Scler. 21, 1291–1297 (2015).
Pisa, F. E. et al. Reproductive factors and the risk of scleroderma: an Italian case-control study. Arthritis Rheum. 46, 451–456 (2002).
Patas, K., Engler, J. B., Friese, M. A. & Gold, S. M. Pregnancy and multiple sclerosis: feto-maternal immune cross talk and its implications for disease activity. J. Reprod. Immunol. 97, 140–146 (2013).
Straub, R. H., Buttgereit, F. & Cutolo, M. Benefit of pregnancy in inflammatory arthritis. Ann. Rheum. Dis. 64, 801–803 (2005).
Voskuhl, R. R. et al. Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 15, 35–46 (2016).
Engler, J. B. et al. Glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy. Proc. Natl Acad. Sci. USA 114, E181–E190 (2017).
Sunami, R., Komuro, M., Yuminamochi, T., Hoshi, K. & Hirata, S. Fetal cell microchimerism develops through the migration of fetus-derived cells to the maternal organs early after implantation. J. Reprod. Immunol. 84, 117–123 (2010).
Mahmood, U. & O'Donoghue, K. Microchimeric fetal cells play a role in maternal wound healing after pregnancy. Chimerism 5, 40–52 (2014).
Kara, R. J. et al. Fetal cells traffic to injured maternal myocardium and undergo cardiac differentiation. Circ. Res. 110, 82–93 (2012).
Roy, E. et al. Biphasic recruitment of microchimeric fetal mesenchymal cells in fibrosis following acute kidney injury. Kidney Int. 85, 600–610 (2014).
Santos, M. A., O'Donoghue, K., Wyatt-Ashmead, J. & Fisk, N. M. Fetal cells in the maternal appendix: a marker of inflammation or fetal tissue repair? Hum. Reprod. 23, 2319–2325 (2008).
Seppanen, E., Fisk, N. M. & Khosrotehrani, K. Pregnancy-acquired fetal progenitor cells. J. Reprod. Immunol. 97, 27–35 (2013).
Zeng, X. X. et al. Pregnancy-associated progenitor cells differentiate and mature into neurons in the maternal brain. Stem Cells Dev. 19, 1819–1830 (2010).
Nassar, D. et al. Fetal progenitor cells naturally transferred through pregnancy participate in inflammation and angiogenesis during wound healing. FASEB J. 26, 149–157 (2012).
Nguyen Huu, S. et al. Maternal neoangiogenesis during pregnancy partly derives from fetal endothelial progenitor cells. Proc. Natl Acad. Sci. USA 104, 1871–1876 (2007).
Roy, E. et al. Specific maternal microchimeric T cells targeting fetal antigens in β cells predispose to auto-immune diabetes in the child. J. Autoimmun. 36, 253–262 (2011).
Leveque, L. et al. Selective organ specific inflammation in offspring harbouring microchimerism from strongly alloreactive mothers. J. Autoimmun. 50, 51–58 (2014).
Nelson, J. L. et al. Maternal microchimerism in peripheral blood in type 1 diabetes and pancreatic islet β cell microchimerism. Proc. Natl Acad. Sci. USA 104, 1637–1642 (2007).
Ye, J., Vives-Pi, M. & Gillespie, K. M. Maternal microchimerism: increased in the insulin positive compartment of type 1 diabetes pancreas but not in infiltrating immune cells or replicating islet cells. PLoS ONE 9, e86985 (2014).
Khosrotehrani, K. et al. Presence of chimeric maternally derived keratinocytes in cutaneous inflammatory diseases of children: the example of pityriasis lichenoides. J. Invest. Dermatol. 126, 345–348 (2006).
Stevens, A. M., Hermes, H. M., Rutledge, J. C., Buyon, J. P. & Nelson, J. L. Myocardial-tissue-specific phenotype of maternal microchimerism in neonatal lupus congenital heart block. Lancet 362, 1617–1623 (2003).
von Hoegen, P., Sarin, S. & Krowka, J. F. Deficiency in T cell responses of human fetal lymph node cells: a lack of accessory cells. Immunol. Cell Biol. 73, 353–361 (1995).
Petit, T. et al. Detection of maternal cells in human fetal blood during the third trimester of pregnancy using allele-specific PCR amplification. Br. J. Haematol. 98, 767–771 (1997).
Srivatsa, B., Srivatsa, S., Johnson, K. L. & Bianchi, D. W. Maternal cell microchimerism in newborn tissues. J. Pediatr. 142, 31–35 (2003).
Touzot, F. et al. Massive expansion of maternal T cells in response to EBV infection in a patient with SCID-Xl. Blood 120, 1957–1959 (2012).
Arvola, M. et al. Immunoglobulin-secreting cells of maternal origin can be detected in B cell-deficient mice. Biol. Reprod. 63, 1817–1824 (2000).
Wrenshall, L. E., Stevens, E. T., Smith, D. R. & Miller, J. D. Maternal microchimerism leads to the presence of interleukin-2 in interleukin-2 knock out mice: implications for the role of interleukin-2 in thymic function. Cell. Immunol. 245, 80–90 (2007).
von Mutius, E. The microbial environment and its influence on asthma prevention in early life. J. Allergy Clin. Immunol. 137, 680–689 (2016).
Elahi, S. et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504, 158–162 (2013).
Tian, Y., Kuo, C. F., Akbari, O. & Ou, J. H. Hepatitis B virus persistence in offspring after vertical transmission is driven by macrophages that are altered by virus e antigen in mother. Immunity 44, 1204–1214 (2016).
Berry, S. M. et al. Association of maternal histocompatibility at class II HLA loci with maternal microchimerism in the fetus. Pediatr. Res. 56, 73–78 (2004).
Kaplan, J. & Land, S. Influence of maternal–fetal histocompatibility and MHC zygosity on maternal microchimerism. J. Immunol. 174, 7123–7128 (2005).
Wienecke, J. et al. Pro-inflammatory effector Th cells transmigrate through anti-inflammatory environments into the murine fetus. Placenta 33, 39–46 (2012).
Nijagal, A. et al. Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. J. Clin. Invest. 121, 582–592 (2011).
Saadai, P. & MacKenzie, T. C. Increased maternal microchimerism after open fetal surgery. Chimerism 3, 1–3 (2012).
Delassus, S. & Cumano, A. Circulation of hematopoietic progenitors in the mouse embryo. Immunity 4, 97–106 (1996).
Mikkola, H. K. & Orkin, S. H. The journey of developing hematopoietic stem cells. Development 133, 3733–3744 (2006).
Gibbons, D. et al. Interleukin-8 (CXCL8) production is a signatory T cell effector function of human newborn infants. Nat. Med. 20, 1206–1210 (2014).
Kinder, J. M. et al. Tolerance to noninherited maternal antigens, reproductive microchimerism and regulatory T cell memory: 60 years after 'evidence for actively acquired tolerance to Rh antigens'. Chimerism 6, 8–20 (2015).
Stevens, A. M. Maternal microchimerism in health and disease. Best Pract. Res. Clin. Obstet. Gynaecol. 31, 121–130 (2016).
Leveque, L. & Khosrotehrani, K. Feto-maternal allo-immunity, regulatory T cells and predisposition to auto-immunity: does it all start in utero? Chimerism 5, 59–62 (2014).
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.
The authors declare no competing financial interests.
- 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.
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.
About this article
Cite this article
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
Journal of Neuroinflammation (2021)
Bone Marrow Transplantation (2021)
Cellular and Molecular Life Sciences (2021)
Scientific Reports (2020)
Seminars in Immunopathology (2020)