Like shoppers in search of the perfect pair of jeans,
the body's special immune system cells apparently have
assistants that help them rapidly "try on" different pieces
of a microbe to find one piece that's shaped just right to
fit their cellular skins, Johns Hopkins scientists
report.
Working with flu viruses to see how these sentinel
cells work, the Johns Hopkins team discovered that they
first feel out a microbe's chemical "shape" until they find
a section that fits tightly into grooves on their
surfaces.
"It turns out that these immune cells do this very
well with a bit of help from a protein assistant that gets
rid of ill-fitting microbe parts to speed up the trying-on
process," said Scheherazade Sadegh-Nasseri, associate
professor of
pathology,
biophysics and
biophysical chemistry in the School of Medicine. A
report on the work appears in the January edition of
Nature Immunology.
Researchers long have known that the immune system
needs the "assistant" protein DM to set up the infectious,
recognizable part of a germ — the antigen — so
that the anti-infectious attack can begin. Cells missing DM
can't do this at all. The new Johns Hopkins work shows that
they actually oversee the selection of the best-fitting
antigen, too.
In experiments measuring the length of time an antigen
stays stuck, DM makes sure an infected cell holds onto a
microbe long enough to catch the attention of immune cells
in the first place, Sadegh-Nasseri said.
To uncover DM's expanded job, Sadegh-Nasseri isolated
a protein antigen from the flu virus as a test case and
found that cells with DM normally hold on for about six
days, long enough for symptoms like sniffles and fever, as
signs of immune battle, to develop. When they removed DM
from normal cells, the cells did not bind the flu antigen
at all. Later, when they mutated the antigen-binding part
of the cell, the flu antigen "fell off" after only 10
minutes.
When the scientists studied the 3-D shape of the part
of the cell that tries on the antigen, they discovered that
the antigen fell off after 10 minutes whether DM was there
or not, but only when one specific chemical bond was
disrupted.
"DM somehow alters this chemical bond to make antigens
fall off a thousand times faster than usual,"
Sadegh-Nasseri said. "We couldn't believe our eyes when we
saw it." Ill-fitting antigens were kicked off in 10 minutes
and replaced. Better-fitting antigens, such as the flu
antigen, held on for days.
"We think that as the cell tries each of the thousands
of different antigens found on an invading microbe, DM
monitors how well each antigen fits by somehow disrupting
this special chemical bond," Sadegh-Nasseri said. "Somehow,
the better-fitting ones are resistant to DM's assault and
stay stuck; these antigens ultimately are presented to
immune cells to start the infection-fighting battle.
"Just like trying on those designer jeans, if the
jeans feel better with the top button undone, it's probably
not the best fit," she added.
The research was funded by the National Institutes of
Health.
Authors on the paper are Kedar Narayan, Chih-Ling
Chou, AeRyon Kim, Isamu Hartman, Sarat Dalai, Stanislav
Khoruzhenko and Sadegh-Nasseri, all of Johns Hopkins.
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