Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells

Abstract

SUMMARY Exposure to maternal tissue during in utero development imprints tolerance to immunologically foreign non-inherited maternal antigens (NIMA) that persists into adulthood. The biological advantage of this tolerance, conserved across mammalian species, remains unclear. Here we show that maternal cells which establish microchimerism in female offspring during development promote systemic accumulation of immune suppressive regulatory T cells (Tregs) with NIMA specificity. NIMA-specific Tregs expand during pregnancies sired by males expressing alloantigens with overlapping NIMA specificity, thereby averting fetal wastage triggered by prenatal infection and non-infectious disruptions of fetal tolerance. Therefore, exposure to NIMA selectively enhances reproductive success in second-generation females carrying embryos with overlapping paternally inherited antigens. These findings demonstrate that genetic fitness, canonically thought to be restricted to Mendelian inheritance, is enhanced in female placental mammals through vertically transferred maternal cells that promote conservation of NIMA and enforce cross-generational reproductive benefits.

An Immunological Perspective on Neonatal Sepsis

“…Using transgenic mice, researchers have been able to show a systemic accumulation of NIMA-specific regulatory T cells in female offspring. Furthermore, micro-chimerism resulting from the persistence of maternal cells in the fetus not only increased fetal tolerance but also improved reproductive fitness in pregnancies sired by males with shared NIMA specificity [30]. These data potentially highlight a mechanism ensuring a successful pregnancy, although it is unclear how faulty tolerance mechanisms might play a role in the initiation of preterm labor in humans.…”

Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance

“…How such rare cells go on to mediate a tolerogenic impact on later fetal survival in adult female hosts (3,4) and on transplant survival in males and females (5,6,23,24), while causing an increased tempo of acute rejection episodes (5), has been a major conundrum. …”

“…Conversely, maternal microchimerism (MMc), common to all mammals, imposes a partial form of immunologic tolerance. Female offspring gain cross-generational fitness in the form of acquired resistance to loss of a fetus bearing inherited paternal antigens (IPAs) identical to her noninherited maternal antigens (NIMAs) (3,4). MMc also has a strong impact in transplantation.…”

THE ROLE OF THE DIFFERENT SUBPOPULATIONS OF CD4⁺Т LYMPHOCYTES DURING PREGNANCY

“…Active interaction of these subpopulations may underlie a multilevel control of immune tolerance maintenance in the mother-fetus system, which is based on duplication of functions and multiple direct and reverse relations. A relatively new mechanism of immune tolerance formation through reciprocal transplacental migration of Tregs and their colonization of lymph nodes, which was named maternal-fetal microchimerism, should be taken into account [27,30,47]. It also should be noted that localized in the decidua and regional lymph nodes the immune system cells are also under active effect of trophoblast and decidua stroma cells.…”