How Do T Cells Find Foreign
Invaders? Other Immune Cells Show Them Von Andrian’s Bowditch Lecture
Features Video Of Live Immune System At Work, Has Implications For Vaccine
Development
SAN FRANCISCO (April 2, 2006) – The saying goes that a
picture is worth a thousand words. But these pictures could one day be worth
much more -- the lives saved by the development of new vaccines.
Harvard University researcher Ulrich H. von Andrian
showed the immune system of a live mouse being challenged by a foreign
microbe during a presentation at Experimental Biology 2006. The footage gave
many of the physiologists in attendance their first glimpse of these cells
in action in a live animal.
Scientists have long studied the immune system,
imagining how many of the component cells proceed on their microscopic
duties. Until recently, there has been no way to directly view much of this
complex cellular teamwork in vitro and in real time.
The von Andrian videos provided a real-time look at
what happens inside a mouse lymph node when a foreign microbe enters the
body. The videos were made possible by recent technological advances
together with techniques the von Andrian lab developed.
*Henry Pickering Bowditch Award Lecture:
“Migrants on a single-minded mission: How T cells find their antigen,”
5:45 p.m., Sunday, April 2, Room 134, Convention Center Room 134.
Speaker: Ulrich H. von Andrian, Harvard Medical School and CBR Institute for
Biomedical Research, Boston, MA.
The American Physiological Society presents the
Henry Pickering Bowditch Award for early-career achievement to a scientist
younger than 42, whose accomplishments are both original and outstanding. It
is the Society’s second highest award.
A medical doctor who also earned a Ph.D. in neurology
and neurosurgery, von Andrian was originally interested in microvascular
integrity in the brain. But during a fellowship early in his career, he
discovered his interest in the immune system, and made it his life’s work.
Rare footage highlights
presentation
A live mouse’s T cells and dendritic cells are the
stars of the von Andrian videos, as the immune system marshals its forces to
fight off a new infection. His laboratory hones in on how dendritic cells --
professional antigen-presenting cells -- teach T cells to respond to an
infection.
“This had never been observed in a live system before
we obtained it,” von Andrian said of the footage “Before this, what had gone
on inside the lymph node was largely a black box.” His team published their
first work using the new approach in January 2004.
von Andrian’s research has focused on how
-
tissues of the immune system recruits T cells
-
dendritic cells get to the right spot, the lymph node, to
meet the T-cells
-
T cells and antigen-presenting cells find each other once in
the lymph node
-
dendritic cells “educate” the T cells while in the lymph
node
-
T cell and dendritic cell interactions change over time
In addition, the research focuses on how T cells, after
their “education” is complete, migrate to effector sites elsewhere in the
body to eliminate pathogens or tumors, but also may cause inflammatory
diseases, von Andrian said.
Dendritic cells teach, T
cells learn
“We specialize in various types of intravital
microscopy to find out how leukocytes -- the white blood cells of the immune
system that fight infection -- find their way around the body and how they
communicate with other cells,” von Andrian explained. “My lab is interested
in leukocyte recruitment and trafficking, particularly in the lymph nodes.”
The lymph nodes are the school, the dendritic cells the
teachers and the T cells the students, von Andrian explained. Dendritic
cells find foreign invaders, rip them apart and bring the pieces (antigens)
via the lymphatic system to the nearest lymph node. When the dendritic cell
arrives at the lymph node, it presents the dismembered invader to the T and
B white blood cells in a way that rings the alarm about the intruder.
“The dendritic cells alert the T cells that there is
something foreign entering the body,” von Andrian explained. “They tell the
T cells what to do, how to respond. We have known about some aspects of this
process from tissue culture studies, but this has never been observed before
in vivo. That has largely been a black box,” he said.
His group has explored the first days after a T cell
encounters the one antigen it will learn to recognize, von Andrian said.
During this time interval, T cells first migrate rapidly and touch every
dendritic cell for only a few minutes. This initial phase lasts about eight
hours. Then the T cells pick one antigen-presenting dendritic cell and
sticks to it for many hours.
After one day, the T cells disengage from the dendritic
cell and begin to rapidly reproduce. About three days later, they depart
from the lymph node on their search-and-destroy mission.
Homing in on the target
T cells patrol the body by hitching a ride in the
blood, methodically stopping at each lymph node like a night security guard
making the rounds and checking the doors. There are dendritic cells in the
lymph nodes, waiting to present antigens in a way the T cells can recognize.
Each T cell recognizes only one antigen, but preserves
that knowledge in its progeny. On average there are 6,000 T cells
circulating in the human body that recognize a given antigen. Another 6,000
recognize a different antigen, etc. The human body is estimated to contain
25-100 million distinct T cell clones, he said.
When dendritic cells capture a foreign invader and
bring it to the lymph node, many T cells stop by before one is able to
recognize it. “The system, while cumbersome, works because of the amazing
trafficking where they circle around and look for the presence of anything
that might tickle their antigen receptor,” von Andrian said.
If the T cells don’t recognize the antigen, they hop
back in the blood stream and head for the next lymph node. T cells and B
cells can live for months, repeating this process and then passing the
information on to their successors. The interaction between T cells and
dendritic cells in the lymph node changes over time, von Andrian said.
“It’s nice that the T cell learns to recognize the
antigen, but that doesn’t get rid of the microbe that has entered the body,”
von Andrian said. He traced the path of the educated T cells leaving the
lymph node, when they become known as effector cells. In addition, von
Andrian addressed how these T cells kill those cells they identified as
harboring a pathogen without going on a rampage and annihilating everything
in sight.
“There must be a control mechanism that can keep these
cytotoxic cells in check,” von Andrian noted. The immune system does this by
creating regulatory T cells to control the effector cells, he said. Previous
research had shown that the regulatory T cells can also receive their
education in the lymph node before proliferating and entering the blood
stream.
May lead to vaccines
“The events I have described are at the heart of any
vaccination,” von Andrian said. “We really don’t understand very well what
makes a good vaccine or a bad vaccine.” Many pathogens take advantage of
the lymph system to gain access to the body, he noted, including pathogens
used in biological warfare, such as anthrax, or yersinia pestis, the
agent that causes the plague.
Bubonic plague, for instance, starts with a flea that
deposits a few bacteria, which travel via the lymphatic system to the lymph
node and proliferate to huge numbers. One of the puzzles von Andrian has
been working on, is how foreign invaders manage to proliferate in the very
area where the immune system is marshaling its troops.
“So understanding how these (foreign) cells survive in
the lion’s den of the lymph node might allow us develop strategies to combat
infections,” von Andrian said. “Somehow, they do this without ringing the
alarm bells. Possibly we could manipulate the process to ring the alarm bell
for the immune system when it fails to recognize the danger.”
Technological leap makes
it possible
Intravital microscopy, invented in the early 19th
century, allows scientists to look at the tissues and cells of live animals.
The technology has been in use for generations. But particularly advanced
and powerful multi-photon microscopes using infrared beams to image
fluorescent cells in living tissues became commercially available in the
late 1990s.
That prompted von Andrian to embark on a project to use
the technology to study the immune system. He set up his lab at the CBR
Institute and developed a strain of mouse that has fluorescent T-cells.
“We are among a handful of labs which started to do
this at the same time,” von Andrian said of using the technology to study
the immune system. The microscopes produce optical sections through solid
organs, similar to a CT-scan. Hundreds, even thousands of these sections are
assembled into digital time-lapse videos to generate a 3-dimensional look at
an immune response in real time.
The organism remains intact, providing a live look at
what is happening in the immune system. The challenge in adapting the
technology was that it takes 15-30 seconds to generate the necessary series
of photographs to create the 3-dimensional footage and the animal must
remain perfectly still for it to work.
It took a year to figure out how to keep the
anesthetized animal from moving, he said. Others have also worked to develop
and advance the technology, von Andrian said. His lab’s distinction was in
adapting the technology for use in lymphoid organs in live animals.
Editor’s Note: For
further information or to schedule an interview with a member of
the research team, please contact Christine Guilfoy at the APS newsroom @
415.905.1024 (March 31-April 5); 978.290.2400 (cell), 301.634.7253
(office), or
cguilfoy@the-aps.org; or Donna Krupa or (703) 967-2751 (cell) or
(301) 634-7209 (office).
Go to
http://www.faseb.org/meetings/eb2006/call/ and click on “Searchable
Program Planner and Itinerary Builder to find the searchable online program
for EB.
* * *
The
American Physiological Society was founded in 1887 to foster basic and
applied bioscience. The Bethesda, Maryland-based society has more than
10,000 members and publishes 14 peer-reviewed journals containing almost
4,000 articles annually.
APS
provides a wide range of research, educational and career support and
programming to further the contributions of physiology to understanding the
mechanisms of diseased and healthy states. In May 2004, APS received
the Presidential Award for Excellence in Science,
Mathematics and Engineering Mentoring (PAESMEM).
# # #
Experimental Biology is an annual
scientific meeting convened by the Federation of American Societies of
Experimental Biology, including the American Physiological Society (APS)
and other biomedical societies. The meeting features “nominated” lectures,
symposia, research presentations, awards, a job placement center, and an
exhibit of scientific equipment, supplies, and publications. This year’s
participating Societies are APS, American Association of
Anatomists, American Society for Biochemistry and Molecular Biology,
American Society for Investigative Pathology, American Society for
Nutritional Sciences, and the American Society for Pharmacology and
Experimental Therapeutics.
