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How rejection is rejected

January 22, 2013


Ultrasound image of fetal feet.

Research at the University of Minnesota points to a population of immune cells that may be enlisted in the fight against miscarriage, pre-eclampsia, and other complications of pregnancy.

The story behind fetal protection from rejection

The mystery has lingered since the dawn of immunology: Why doesn't a woman's body reject a fetus?

A University of Minnesota team has recently found a short answer. It comes down to a specific type of immune cell whose job is to suppress other immune cells that would reject a fetus.

During pregnancy the population of these cells, called Tregs (formally FOXP3+ regulatory T cells), expands 100-fold. Finding their key role gives medical science a basis for developing therapies to prevent recurrent miscarriages and inflammatory diseases of pregnancy, notably pre-eclampsia.

The work, led by M.D./Ph.D. student Jared Rowe, has been published in the journal Nature.

"It was previously known, because of research in mice by [former U of M professor Sing Sing Way], our other colleagues, and me, that Tregs in general were expanded in numbers in pregnancy," says Rowe, who has since received his doctorate and is now working toward an M.D. "They expanded by 50 percent, and the expansion was essential to maintaining pregnancy in mice."

Their work showed that in mouse pregnancies, this behavior of Tregs exactly mirrors the behavior of Tregs found by other researchers in healthy human pregnancies.

"In our new paper, we show that this [overall] 50 percent rise in Tregs was actually due to a 100-fold increase in Tregs specific for the fetus whose function is to protect the baby from the mother's immune system," Rowe explains.

How to tell a fetus—and what to do about it

As a fetus forms, it produces molecules unique to it called fetal antigens. Circulating in the maternal blood are Tregs that recognize and respond only to fetal antigens. These Tregs quickly multiply and suppress the activity of "effector" T cells that also recognize the fetal antigens and would attack cells containing them.

Close to home

According to the Minnesota Department of Health, in 2010 the state saw 352 fetal deaths (only those of 20 weeks or more are reported). Also, there were 302 births in which the mother had eclampsia (0.4 percent), compared to 68,105 births with none.

This ability of Tregs lasted at least 100 days after birth, Rowe says. In other words, the maternal Tregs remembered the fetal antigens even in the absence of pregnancy. During a second pregnancy, their memory allowed them to expand faster and more than 100-fold and to provide better protection.

Ordinarily, memories of foreign antigens are formed by T cells that attack the cells (or viruses) that bear them. Memory fuels a more vigorous immune response the second time around, and this is the basis of protective vaccines. 

"But this is the first naturally occurring system that primes the memory development of Tregs," Rowe notes. "If you can get Tregs to form a suppressive memory, these findings could be expanded to protect against autoimmune diseases like lupus, rheumatoid arthritis, and multiple sclerosis, where the immune system attacks one's own body, and this may also have implications for transplantation."

Imperfect protection

The observation by Rowe and his colleagues that subsequent pregnancies were less likely to suffer rejection is well known to obstetricians, who have noted lower rates of complications in later pregnancies. But this added protection holds only if the father remains the same.

Jared Rowe.
Jared Rowe

"This implies something about the father, and it's suggestive of fetal antigen," he says. "We showed that fetal-specific Treg memory formation could explain this clinical observation."

We all make antigens—usually proteins or protein-carbohydrate complexes—unique to us that allow our immune system to identify our tissues as "self" and others' as "foreign."

A fetus, too, makes antigens, under the direction of genes from its father and mother. But if a second fetus's father is different, so are the paternally derived antigens, and it's back to square one for the mother's Tregs that protect the fetus. (Maternally derived antigens are seen as "self," not "fetus.")

Also, in recurrent miscarriages and inflammatory diseases of pregnancy like pre-eclampsia, the large increase in Tregs fails to occur. The therapy available to obstetricians for pre-eclampsia or miscarriage is to deliver the baby, Rowe says. 

"It's not known why the increase in Tregs fails," he says. "But if we can find a way to strengthen the Treg activity, we can prevent these conditions. Being able to manipulate/research the fetal-specific Tregs promises to unlock these possibilities." 

Contact the writer at morri029@umn.edu

Tags: Academic Health Center

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Jared Rowe conducted his doctoral studies under the supervision of Sing Sing Way, M.D., Ph.D., a faculty member in the departments of pediatrics and microbiology; he is now at Cincinnati Children's Hospital Medical Center.

Related Links

Jared Rowe

Department of Pediatrics

Academic Health Center