eNews August 19, 2015

Reproductive Fitness Extends Over Multiple Generations

NIMA and microchimeric maternal cells

Successful pregnancies require that mothers develop tolerance to paternal-derived fetal antigens. Otherwise, the developing fetuses would be recognized by the mother’s immune system as “non-self” and destroyed. Fetal survival is even less straightforward because previous research has shown that fetuses are exposed to a diverse collection of non-inherited maternal antigens (NIMA), too. NIMA are presented throughout development, and may include antigens to which the mother has been previously exposed, or antigens derived from molecules or cell surface markers expressed by other individuals. In a recent study published in Cell, a team of researchers led by Dr. Sing Sing Way at Cincinnati Children’s Hospital hypothesized that NIMAs lead to the generation of microchimeric maternal cells that persist throughout adulthood, and that these cells promote the development of immune-suppressive allogeneic regulatory T cells (Tregs). The study demonstrates that these allogeneic Tregs increase the success of second-generation pregnancies by suppressing immune reactions to other paternally-presented antigens and expands our understanding of how reproductive fitness in mammals evolved.

Figure 1. A cross-generational model of reproductive fitness. Microchimeric maternal cells in female offspring provide tolerance for pregnancies sired by males with cognate NIMA specificity.

Transgenes and MHC haplotypes can serve as surrogate NIMAs to examine microchimerism

To confirm the persistence of NIMA tolerance in offspring, the researchers mated transgenic female mice constitutively expressing a transmembrane fusion protein consisting of ovalbumin (OVA) linked to a variant of the H2 I-Eα protein to non-transgenic males. In the progeny of this cross and through subsequent crosses with non-transgenic mice, the transgenic fusion protein became a traceable NIMA in mice that did not inherit the transgene though the identification of a subset of Foxp3+ Tregs that recognized either the I-Eα variant or OVA.

In order to test their hypothesis that microchimeric maternal cells increase the success rate of second-generational pregnancies, the researchers employed a directed breeding approach between inbred strains of mice that carried mismatched MHC haplotypes. The mice used, included:

  • C57BL/6J - H-2b; CD45.2+ (000664)
  • BALB/cJ - H-2d (000651)
  • CBA/J - H-2k (000656)
  • B6.C-H2d/bByJ - H-2d (000359)
  • B6.Ak-H2k/J - H-2k (001895)
  • B6.SJL-PtprcaPepcb/BoyJ - H-2b; CD45.1+ (002014)
Controlled breeding between these strains led to hybrid or homozygous mice that expressed defined MHC alleles and carried NIMA-specific microchimeric maternal cells. The researchers subsequently breed female progeny of these crosses to males with matching or non-matching MHC alleles, and measured breeding success and pup resorption rates. Fetal wastage and pup resorption were significantly reduced in pairs that had complementary NIMA and paternal antigens, in both the presence and absence of additional infection with L. monocytogenes, which was included to amplify immune reactivity. Further, ablation of NIMA-carrying Treg cells using diphtheria toxin treatment in mice that also carried a Treg-specific diphtheria toxin receptor (DTR) (derived from crossing the mice to B6.129(Cg)-Foxp3tm3(DTR/GFP)Ayr/J (016958) resulted in an increase in the rate of pup resorption in NIMA/paternal matched pregnancies.

These data support an evolutionary model of reproductive fitness in which maternal antigens that are not genetically passed down to daughter progeny promote fetal tolerance for second-generation offspring sired by males with matched antigen specificity. Further, the role of NIMA and microchimeric maternal cells in pregnancy success may lead to improved assisted reproductive technologies and immune interventions for patients.