Kofi
2011-01-03 02:35:36 UTC
http://www.sciencedaily.com/releases/2010/12/101216165519.htm
Human Fetal Immune System Arises from Entirely Different Source Than
Adult Immune System
ScienceDaily (Dec. 17, 2010) UCSF researchers have shown for the first
time that the human fetal immune system arises from an entirely
different source than the adult immune system, and is more likely to
tolerate than fight foreign substances in its environment.
The finding could lead to a better understanding of how newborns respond
to both infections and vaccines, and may explain such conundrums as why
many infants of HIV-positive mothers are not infected with the disease
before birth, the researchers said.
It also could help scientists better understand how childhood allergies
develop, as well as how to manage adult organ transplants, the
researchers said. The findings are described in the Dec. 17 issue of
Science.
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 unveiled an entirely different immune
system in the fetus at mid-term that is derived 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," said Joseph M. McCune, MD, PhD, a professor
in the UCSF Division of Experimental Medicine who is a co-senior author
on the paper. "After birth, a new immune system arises from a different
stem cell that instead has the job of fighting everything foreign."
The team previously had discovered that fetal immune systems are highly
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.
The adult immune system, by contrast, 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 'see' those threats, because it didn't
respond to them," said Jeff E. Mold, first author on the paper and a
postdoctoral fellow in the McCune laboratory. "What we found is that
these fetal immune cells are highly prone to 'seeing' 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"- those 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 research found.
The team set out to assess 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, refuting the
notion that fetal cells don't recognize outsiders. But 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.
Researchers then sorted 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 appears 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.
Co-authors of the study include Trevor D. Burt, Jose M. Rivera, Sofiya
Galkina and co-senior author Cheryl A. Stoddart, all from the UCSF
Department of Medicine, Division of Experimental Medicine; Jakob
Michaelsson, from the Center for Infectious Medicine, Karlinska
Institutet, Stockholm, Sweden; and Shivkumar Venkatasubrahmanyam and
Kenneth Weinberg, of the Center for Biomedical Informatics Research and
Division of Hematology/Oncology, respectively, at Stanford University,
Palo Alto, Calif. Burt also is affiliated with the UCSF Division of
Neonatology in the Department of Pediatrics.
Support for this work was provided by grants from the National
Institutes of Health and from the Harvey V. Berneking Living Trust.
------------------------------------------------------------------------
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily
staff) from materials provided by University of California - San
Francisco.
------------------------------------------------------------------------
Journal Reference:
1. J. E. Mold, S. Venkatasubrahmanyam, T. D. Burt, J. Michaelsson, J. M.
Rivera, S. A. Galkina, K. Weinberg, C. A. Stoddart, J. M. McCune. Fetal
and Adult Hematopoietic Stem Cells Give Rise to Distinct T Cell Lineages
in Humans. Science, 2010; 330 (6011): 1695 DOI: 10.1126/science.1196509
Human Fetal Immune System Arises from Entirely Different Source Than
Adult Immune System
ScienceDaily (Dec. 17, 2010) UCSF researchers have shown for the first
time that the human fetal immune system arises from an entirely
different source than the adult immune system, and is more likely to
tolerate than fight foreign substances in its environment.
The finding could lead to a better understanding of how newborns respond
to both infections and vaccines, and may explain such conundrums as why
many infants of HIV-positive mothers are not infected with the disease
before birth, the researchers said.
It also could help scientists better understand how childhood allergies
develop, as well as how to manage adult organ transplants, the
researchers said. The findings are described in the Dec. 17 issue of
Science.
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 unveiled an entirely different immune
system in the fetus at mid-term that is derived 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," said Joseph M. McCune, MD, PhD, a professor
in the UCSF Division of Experimental Medicine who is a co-senior author
on the paper. "After birth, a new immune system arises from a different
stem cell that instead has the job of fighting everything foreign."
The team previously had discovered that fetal immune systems are highly
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.
The adult immune system, by contrast, 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 'see' those threats, because it didn't
respond to them," said Jeff E. Mold, first author on the paper and a
postdoctoral fellow in the McCune laboratory. "What we found is that
these fetal immune cells are highly prone to 'seeing' 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"- those 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 research found.
The team set out to assess 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, refuting the
notion that fetal cells don't recognize outsiders. But 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.
Researchers then sorted 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 appears 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.
Co-authors of the study include Trevor D. Burt, Jose M. Rivera, Sofiya
Galkina and co-senior author Cheryl A. Stoddart, all from the UCSF
Department of Medicine, Division of Experimental Medicine; Jakob
Michaelsson, from the Center for Infectious Medicine, Karlinska
Institutet, Stockholm, Sweden; and Shivkumar Venkatasubrahmanyam and
Kenneth Weinberg, of the Center for Biomedical Informatics Research and
Division of Hematology/Oncology, respectively, at Stanford University,
Palo Alto, Calif. Burt also is affiliated with the UCSF Division of
Neonatology in the Department of Pediatrics.
Support for this work was provided by grants from the National
Institutes of Health and from the Harvey V. Berneking Living Trust.
------------------------------------------------------------------------
Story Source:
The above story is reprinted (with editorial adaptations by ScienceDaily
staff) from materials provided by University of California - San
Francisco.
------------------------------------------------------------------------
Journal Reference:
1. J. E. Mold, S. Venkatasubrahmanyam, T. D. Burt, J. Michaelsson, J. M.
Rivera, S. A. Galkina, K. Weinberg, C. A. Stoddart, J. M. McCune. Fetal
and Adult Hematopoietic Stem Cells Give Rise to Distinct T Cell Lineages
in Humans. Science, 2010; 330 (6011): 1695 DOI: 10.1126/science.1196509