May 26, 2000
Immune System Switch Controls Destiny of White Blood Cells
By increasing or decreasing levels of a specific protein,
researchers can control the developmental destiny of white blood
cells.
The finding represents the first evidence that mammalian immune
system cells respond to such a dual control mechanism. The discovery
raises the possibility that scientists might be able to use the
developmental switch to manipulate the immune system to produce
specific disease-fighting cells. Furthermore, throwing the switch by
using drugs or gene therapy might jump-start the proper development of
immature blood cells whose maturation is stalled in certain
cancers.
“We believe that development of different lineages of blood cells is triggered by a combination of particular sets of transcription factors and their levels relative to one another.”
Harinder Singh
In an article in the May 26, 2000, issue of Science, Howard
Hughes Medical Institute investigator Harinder Singh and his
colleague Rodney DeKoter report that the concentration of the
transcription factor PU.1 in progenitor immune cells determines whether
those cells become macrophages or B cells.
Transcription factors are proteins that activate genes to transcribe
their information into messenger RNA. Macrophages are white blood cells
that attack bacteria and other invaders by engulfing and digesting
them; while B cells generate antibodies that tag pathogens bearing
foreign proteins, marking them for attack by other immune cells.
In previous studies, Singh and his colleagues at the University of
Chicago showed that knocking out the PU.1 gene in mice
eliminated the ability of such mice to make white blood cells. The
scientists found that PU.1 switched on genes specific to progenitors of
macrophages or B cells that were necessary for their normal
differentiation into mature cells.
"This left us with a puzzle," said Singh. "If this transcription
factor is needed for development of different cell types in the immune
system— each of which expresses very different sets of
genes— how could a single factor participate in regulating these
very diverse programs of gene expression?"
In exploring PU.1's role in development, the researchers created a
method for isolating mutant mouse progenitor blood cells that lacked
PU.1. Once they had harvested the PU.1-deficient cells, they used a
viral vector to shuttle the PU.1 genes back into the cells.
"We found that these cells that were otherwise blocked from
developing any further recovered their ability to differentiate
properly into macrophages or B cells when they received the gene for
PU.1," said Singh.
A striking result of this experiment, said Singh, was that the
resulting macrophages expressed high concentrations of the PU.1
protein, while the B cells expressed low concentrations.
"It was quite a surprise," said Singh. "Although there had been some
reports that PU.1 levels were different in macrophages and B cells, no
one had ascribed any functional significance to that difference."
To explore the functional role of PU.1 levels in immune cell
differentiation, the researchers next raised the level of PU.1 in
normal progenitor cells. They found that higher PU.1 levels effectively
caused the cells to become macrophages, rather than B cells.
And in a third set of experiments, the scientists inserted a
truncated form of the PU.1 protein into cells that lacked PU.1 and
found that this "weakened" transcription factor efficiently rescued the
development of B cells, but not of macrophages.
"Thus, we have shown that a lower concentration or a lower activity
state translates into one developmental outcome for these cells,
turning them into B cells," said Singh. "And conversely, higher
concentrations of the regulator produce macrophages.
"The idea that differing concentrations of a transcription factor
can control the development of different cell types from progenitors
has been an attractive and commonly held view among developmental
biologists," said Singh. "It has been exceedingly difficult, however,
to show that this principle is actually valid in any given
organism."
Singh noted that, while researchers had shown that developing fruit
flies use graded levels of certain transcription factors to control the
generation of different embryonic cell types, "there hasn't been strong
evidence for this mechanism in mammalian systems. Thus, we are
providing good evidence that concentration-based control exists in the
immune system, and of course, in mammals in general."
Singh emphasized that despite PU.1's importance, it is certainly not
the lone determinant of immune cell differentiation.
"We believe that development of different lineages of blood cells is
triggered by a combination of particular sets of transcription factors
and their levels relative to one another," he said.
Understanding how PU.1 controls immune cell development could have
important medical implications, he noted.
"Once we understand the regulatory circuitry that controls immune
cell development, we could exploit that knowledge to develop treatments
that direct progenitor cells to differentiate into particular cell
types for therapeutic purposes," he said.
"Also, many cancers of the immune system involve interruption of
blood cell differentiation. It's possible that drugs or gene therapy
could be developed to increase PU.1 activity to unblock differentiation
of these cancer cells and make them become benign."
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