Pregnancy induced displacement of preexisting microchimeric cells in the absence of maternal B and T cells

Abstract

Bidirectional exchange of cells between mother and fetus occurs during pregnancy, and persistence of these genetically foreign cells establishes long-term microchimerism in both individuals after parturition. Since women can have multiple pregnancies, and all mothers were once daughters themselves, the microchimeric milieu in each woman could theoretically contain cells from a variety of origins, including from their own mothers as well as their babies from each pregnancy. Interestingly and in sharp contrast to this prediction, we recently showed preexisting populations of microchimeric cells are lost following pregnancy and associated with seeding of new fetal microchimeric cells. Complete loss of preexisting microchimeric cells in this context draws parallels to immunological rejection with synchronized elimination of cells and tissues that express defined discordant antigens. This perspective evaluates this provocative hypothesis regarding pregnancy induced rejection of microchimeric cells, including new experimental data comparing microchimerism levels in mice simultaneously lacking B and T cells before pregnancy, and after parturition with primary and secondary pregnancies.

Keywords: B cell; RAG1; T cell; immune tolerance; microchimerism; microchiome; non-inherited maternal antigen; reproductive fitness.

Figure 1

Fetal microchimeric cells displaced after pregnancy despite lack of maternal B and T cells. (A) Mating scheme for Rag1-/- (Jackson laboratory, strain #002216) sired by OVA+ transgenic males allowing identification of microchimeric cells by quantifying OVA+ DNA (primary postpartum) or after secondary pregnancy sired by non-transgenic CBA H-2^k males allowing identification of microchimeric cells by quantifying H-2^k+ DNA (secondary postpartum). (B) Levels of OVA+ DNA specific to OVA+ fetal microchimeric cells or H-2^k+ DNA specific to H-2^k+ fetal microchimeric cells in each tissue among Rag1-/- mice 21 days postpartum after primary allogeneic pregnancy sired by OVA+ H-2^d Balb/c males (filled), or secondary pregnancy sired by H-2^k+ CBA males (open) quantified using DNA extraction and quantitative PCR methods described in reference (26). Each point represents the data from an individual mouse, with colors used to depict data from tissues of the same mouse, and representative of at least two independent experiments each with similar results. Bar, mean ± standard error. *P < 0.05. Mouse figures were prepared using Biorender; graphs and statistics analyzed using Graphpad Prism (Version 10.1).

Figure 2

Maternal microchimeric cells displaced after pregnancy despite lack of maternal B and T cells. (A) Mating scheme for generating Rag1-/- born to OVA+/- mothers transforming OVA into a surrogate NIMA and tracking maternal microchimeric cells after quantifying OVA+ DNA in virgin control or after pregnancy sired by non-transgenic CBA H-2^k males (postpartum). (B) Levels of OVA+ DNA specific to OVA+ maternal microchimeric cells or H-2^k+ DNA specific to H-2^k+ fetal microchimeric cells in each tissue among Rag1-/- NIMA-OVA mice 21 days postpartum after allogeneic pregnancy sired by H-2^k+ CBA males (open) or age-matched virgin Rag1-/- NIMA-OVA mice (filled) quantified using DNA extraction and quantitative PCR methods described in reference (26). Each point represents the data from an individual mouse, with colors used to depict data from tissues of the same mouse, and representative of at least two independent experiments each with similar results. Bar, mean ± standard error. **P < 0.01. Mouse figures were prepared using Biorender; graphs and statistics analyzed using Graphpad Prism (Version 10.1).