Cells from grandma help keep fetus safe

Parents often complain that grandparents meddle in child-rearing. New research suggests that such meddling starts in the womb, where cells from grandma manipulate the mother’s immune system.

Scientists already knew that during pregnancy some cells from the fetus invade the mother, while cells from mom sneak into the offspring. These interloping cells can survive for decades (SN: 11/3/12, p. 12). Some research suggests that fetal cells help mom repair damaged tissues or, on a darker note, promote autoimmune disease (SN Online: 5/10/15). But it’s not clear what a mother’s cells do in her offspring.

Now research with mice suggests that these cells impose a mother’s own self-interest on future generations. Mother’s cells, also known as microchimeric cells, may ensure survival of a mother’s genetic line by manipulating the immune systems of her daughters during pregnancy, researchers from Cincinnati Children’s Hospital report online July 23 in Cell. That manipulation protects fetuses that share the maternal grandmother’s genetic makeup from immune system attack.

Since the 1950s, researchers have had hints that grandmother’s cells play a role in saving fetuses that have different blood types than their mothers’. But other scientists have doubted those findings. The new study, says Trevor Burt, a developmental immunologist at the University of California, San Francisco, “is the first time I’ve seen convincing evidence that microchimerism promotes reproductive health and fitness over generations.”

In the study, immunobiologist Jeremy Kinder and colleagues genetically engineered female mice to carry one copy of a chicken gene for ovalbumin, an egg white protein. Some of the ovalbumin-producing mice’s offspring didn’t inherit the gene, so their own body cells didn’t make the protein. But those offspring carried cells inherited from their mothers that did make the protein. About one in 100,000 to one in 1 million cells in the offspring of the engineered females came from the mother, the team discovered.

Daughters that didn’t inherit the ovalbumin gene were mated to male mice that had it. Any offspring that got the gene from the male should have come under attack from the mother’s immune system. But when the pregnant daughter carried ovalbumin-producing cells from her mother, fetuses making that protein were protected from immune attack.

Microchimeric cells also protected fetuses from miscarriage after infection with a food-poisoning bacterium called Listeria monocytogenes. Infections with that bacterium can lead to miscarriages in people.

Removing the mother’s cells from the daughter erased the protective effect.

Microchimeric cells stimulate production of immune cells called T cells, the researchers found. Specifically, mom’s cells cause the daughter’s immune system to make more T cells that calm the immune system’s reaction to foreign cells. Those T cells recognize any cells carrying the same genes as the grandmother as part of the mother’s body and keep them safe.

On the other hand, microchimeric cells may also prime other immune cells to attack, so that fetuses genetically unlike the grandmother are less likely to survive.

By passing along immune-manipulating cells that favor some fetuses and reject others, mothers may ensure that their daughters have more success with a mate with a similar genetic makeup to the daughter’s mother, says William Burlingham, a transplant immunologist at the University of Wisconsin–Madison. “It’s almost like she’s saying, ‘marry someone like me. It’s for your own good and for the good of your child.’”

This type of cross-generational influence peddling doesn’t fit well with classic genetic inheritance scenarios, says Sing Sing Way, an infectious disease pediatrician who led the research. Mothers and fathers each pass along half of their genes to their offspring. But mothers bypass this law of inheritance by also handing down cells that contain all of her DNA. The transfer is made during pregnancy and reinforced by breast-feeding, the researchers discovered.

Human mothers may not exert quite as much influence as mice do over their daughter’s pregnancies, Burt says. “In mice, they’ve shown it quite nicely, but given the complexities of human genetics, I think the story is much more complex.”