Natural-born killers:
An immunologic enigma solved
BY KRISTIN WEIDENBACH
Side-by-side research
papers featured in the December issue of Immunity resolve
a mystery of basic immunology while suggesting a new way
to improve the success of bone marrow transplantation.
The research conducted
by postdoctoral fellows Markus Uhrberg and Nick Valiante
in the lab of Peter Parham, professor of structural
biology focused on enigmatic white blood cells called
natural killer cells.
Natural killer (NK) cells
have been largely ignored by immunologists drawn to T and
B cells, the big guns of the adaptive immune system. This
obscurity is what inspired the Stanford team to learn
more about the function of these large granular cells,
thought by some to be an archaic remnant of the primitive
mammalian immune system. "The NK cell has always
been the ugly stepchild," said Valiante. "It
was such a black box you knew there had to be something
more there."
NK cells spontaneously
kill abnormal cells in their vicinity. They recognize and
attack tumor cells or those infected by viruses, while
sparing cells that are healthy. But how they distinguish
between healthy and sick cells has been a mystery.
In the newly published
papers, Parham's group presents the first systematic,
experimental evidence validating a leading explanation
for this phenomenon.
The explanation, known as
the missing-self model, was first proposed in 1986. It
holds that a person's NK cells somehow "know"
when a nearby cell lacks some essential component that
characterizes the rest of the cells in that person's
body. Early support for the model came in the late 1980s
when scientists discovered that NK cells have surface
receptors that recognize target molecules on neighboring
cells. These target molecules were the so-called
transplantation antigens the human leukocyte antigens
(HLA) that exist on the surface of almost all cells of
the body and that differentiate an individual's cells
from those of almost everyone else.
Immunologists theorized
that when an NK cell encounters "self" HLA
antigens, it recognizes the target cell as friend, not
foe, and leaves the cell in peace; but if it fails to
detect these antigens, it views the cell as diseased or
an invader, and kills it. This system for recognizing
"self" or "missing self" offered a
compelling explanation of how NK cells distinguish
healthy cells from sick ones, because many tumor cells
and virally infected cells turn off their production of
HLA antigens to escape detection by other cells of the
immune system.
Until now, however, no one
had methodically tested these predictions and provided
definitive evidence that the model actually works.
"The theory was there, but no one had tested it at
the level of the organism," said Valiante.
"Others had tried, but they were looking only at a
single [NK cell-HLA] interaction in many different
individuals. Our approach was to look at only a few
individuals but to look at all possible interactions that
could occur."
Valiante and Uhrberg
analyzed more than 100 single NK cells from each of two
unrelated people who provided blood for the study and
whose "self" HLA antigens were known. Valiante
painstakingly isolated and cultured individual NK cell
clones and documented their killing response to various
"self" antigens. Uhrberg devised a DNA-typing
method to define which receptors were expressed on each
NK cell.
With the new typing
system, the researchers were able to correlate receptor
expression with the cell's ability to recognize
"self" antigens. The results showed that every
NK cell could be inhibited by one or more
"self" HLA antigens. A set of up to 11
different receptors could be displayed on the NK cell
surface in many different combinations. With such an
array of receptors to choose from, each cell was assured
of being able to recognize the relevant "self"
HLA antigens and restrain its natural homicidal urges. If
the "self" component was missing, the abnormal
cell was killed.
The immediate implication
of this work, said Uhrberg, is that NK cells play an
important role in the delicate area of bone marrow
transplantation.
Clinicians are always
careful to match transplant recipients with donors who
have the same HLA antigens. It is well accepted that
introduction of a foreign HLA molecule from the donor
will result in rejection of the grafted tissue. However,
even when there seems to be a good match, the grafted
tissue is sometimes rejected for no apparent reason. The
new research points to the patient's NK cells as a
culprit in such rejections.
If the recipient's NK
cells detect the absence of a "self" HLA
antigen during surveillance of the transplanted tissue,
they will begin killing the donor cells. Therefore, in
order to improve outcomes, donors and recipients need to
be matched not only for their HLA type but also for their
NK cell receptors.
Prospective matching for
these receptors has never been attempted, but the new
research suggests that complementary HLA antigens and NK
cell receptors may be important for better transplant
success and Uhrberg's typing method provides the tool
to achieve it.
"If we can
extrapolate from these two [human] subjects, and I think
we can, by knowing the [NK cell receptor and HLA] types
of donors and recipients we can make pretty accurate
predictions about possible bad effects," Valiante
said.
"Physicians are
constantly asking which factors improve transplantation
outcome," Uhrberg said. "The new data will
encourage people to look for these differences in NK cell
receptors because they could have an influence on
transplantation outcome."
Uhrberg and Valiante
attribute much of the project's success to a melding of
complementary research skills: Valiante's long history in
cellular immunology, Uhrberg's strength in molecular
immunology, and Parham's wealth of experience in HLA
structure and function. A productive collaboration with
Drs. Lewis Lanier and Joseph Philips of DNAX Research
Institute of Molecular and Cellular Biology, in Palo
Alto, provided the final necessary ingredient. Funding
for the project was provided by grants from the National
Institutes of Health and the Leukemia Society of America.
Timing was also crucial,
the researchers agree. "It was the right time to ask
one of the big questions [about NK cells]," said
Valiante. "Three years ago it was not possible to do
these studies. The receptors hadn't been characterized
yet; there were no molecular data."
Now they are both excited
about the publication of their results in Immunity.
Look for the NK cell on
the cover. SR
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