December 21, 2010

New Source of Fetal Immune Cells Found

(Ivanhoe Newswire) -- For the first time ever it is shown that human fetal immune system arises from a completely different source than the adult immune system, and is more likely to tolerate than fight foreign substances in its environment.

This finding could lead to a better understanding of how newborns respond to infections and vaccines, and may explain some mysteries as to why many infants of HIV-positive mothers are not infected with the disease before birth. In addition, it could help scientists better understand how childhood allergies develop, as well as how to manage adult organ transplants.

Until now, the fetal and infant immune system had been thought to be simply an immature form of the adult system, one that responds differently because of a lack of exposure to immune threats from the environment. The new research has revealed an entirely different immune system in the fetus at mid-term that comes from a completely different set of stem cells than the adult system.

"In the fetus, we found that there is an immune system whose job it is to teach the fetus to be tolerant of everything it sees, including its mother and its own organs," Joseph M. McCune, MD, PhD, a professor in the UCSF Division of Experimental Medicine who is a co-senior author on the paper, was quoted as saying. "After birth, a new immune system arises from a different stem cell that instead has the job of fighting everything foreign."

The team had previously discovered that fetal immune systems are very tolerant of cells foreign to their own bodies and hypothesized that this prevented fetuses from rejecting their mothers' cells during pregnancy and from rejecting their own organs as they develop.

In contrast, the adult immune system is programmed to attack anything it considers "other," which allows the body to fight off infection, but also causes it to reject transplanted organs.

"The adult immune system's typical role is to see something foreign and to respond by attacking and getting rid of it. The fetal system was thought in the past to fail to "Ëœsee' those threats, because it didn't respond to them," Jeff E. Mold, first author on the paper and a postdoctoral fellow in the McCune laboratory, was quoted as saying. "What we found is that these fetal immune cells are highly prone to "Ëœseeing' something foreign, but instead of attacking it, they allow the fetus to tolerate it."

The previous studies attributed this tolerance, at least in part, to the extremely high percentage of "regulatory T cells", cells that provoke a tolerant response, in the fetal immune system. At mid-term, fetuses have roughly three times the frequency of regulatory T cells as newborns or adults.

The researchers assessed whether fetal immune cells were more likely to become regulatory T cells. They purified so-called naïve T cells "“ new cells never exposed to environmental assault "“ from mid-term fetuses and adults, and then exposed them to foreign cells. In a normal adult immune system, that would provoke an immune attack response.

They found that 70 percent of the fetal cells were activated by that exposure, compared to only 10 percent of the adult cells, backing the notion that fetal cells don't recognize outsiders. Of those cells that responded, twice as many of the fetal cells turned into regulatory T cells, showing that these cells are both more sensitive to stimulation and more likely to respond with tolerance, Mold said.

The researchers continued by sorting the cells by gene expression, expecting to see similar expression of genes in the two cell groups. In fact, they were vastly different, with thousands of genes diverging from the two cell lines. When they used blood-producing stem cells to generate new cell lines from the two groups, the same divergence occurred.

"We realized they there are in fact two blood-producing stem cells, one in the fetus that gives rise to T cells that are tolerant and another in the adult that produces T cells that attack," Mold said. Why that occurs, and why the immune system seems to switch over to the adult version sometime in the third trimester, remains unknown, McCune said.

Further studies will attempt to determine precisely when that occurs and why, as well as whether infants are born with a range of proportions of fetal and adult immune systems "“ information that could change the way we vaccinate newborns or treat them for such diseases as HIV.

SOURCE: Science, published online December 20, 2010