|Chemical Guidance of T Cells Leads to Immunologic Memory and
In the latest issue of the journal Nature, scientists at the National
Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes
of Health (NIH) describe a new understanding about how long-term immunity works — findings
that may lead to new ways of thinking about how to enhance certain immune responses
and how to improve vaccines.
Led by immunologist Ronald Germain, M.D., Ph.D., the scientists took videos
through a microscope to document what happens inside the lymph nodes of a living
mouse shortly after a vaccination. The videos reveal that the movement of a specific
type of immune cell known as a CD8+ T cell, also called a cytotoxic T cell, is
not random as was previously thought, but instead is guided by chemical signals
released from other cells.
Scientists have long recognized the importance of understanding how CD8+ T cells
move through the lymph nodes and become activated. Once active, CD8+ T cells
roam throughout the body destroying cells infected with bacteria or viruses — a
process known as cell-mediated immunity. When these CD8+ T cells encounter an
infected cell, they unleash a torrent of substances that poke holes in the cell’s
membrane, chew up its proteins and ultimately cause it to die. They also produce
molecules such as interferon-gamma that help activate other immune cells.
After they fight the initial infection, some of these CD8+ T cells remain in
the circulation as memory cells, primed to fight if the host is re-infected with
the same pathogen. Memory cells are key to vaccine strategies being studied for
infectious agents such as HIV. But the CD8+ T cells can only become effective,
long-lived memory cells after they encounter certain other cells in the lymph
node that can activate them.
The new research, conducted largely by senior postdoctoral fellows Flora Castellino,
M.D., and Alex Huang, M.D., Ph.D., with Dr. Germain’s guidance, shows that when
CD8+ T cells enter the lymph node, a combination of specific physical and chemical
cues guides them to sites where they receive activation signals. Specifically,
two molecules known as chemokines help guide them toward the cells that release
these activation signals.
“Understanding the processes whereby CD8+ T cells find their way in the lymph
nodes is important because their activation is essential for eliminating infected
cells and for providing, together with antibodies, long-lasting protection following
vaccinations,” says NIAID Director Anthony S. Fauci, M.D.
The body contains hundreds of millions of CD8+ T cells, but only a tiny fraction
of them become activated during an infection. These are selected because each
CD8+ T cell carries a unique surface protein called a T-cell receptor, which
recognizes only specific antigens (pieces of virus or bacteria that trigger the
immune response). During an infection, CD8+ T cells that recognize antigens from
the infecting pathogen are activated. These antigen-specific CD8+ T cells expand
into a large population of active clones, which then sweep through the body,
hunting down and killing infected cells.
For CD8+ T-cell activation to occur in the lymph node, the cell must encounter
its target antigen — but that antigen must be displayed on the surface
of another immune system cell, called a dendritic cell. Usually a third type
of cell, known as a “helper” T cell, must be involved as well. But how do the
CD8+ T cells find the right dendritic cells presenting the specific antigen they
need to see? Moreover, how do they find the particular dendritic cells that have
been properly stimulated by helper T cells?
Dr. Germain and his colleagues determined that naïve CD8+ T cells do not wander
aimlessly through the lymph node but instead are steered towards areas in which
dendritic cells concentrate. Think of the lymph node as a large airport terminal
and the CD8+ T cells as the arriving passengers, says Dr. Germain. If passengers
know that limo drivers will meet them in the terminal, they will look for their
drivers upon arrival. Rather than hoping to run into each other by chance, the
drivers crowd around the arrival gates and hold up signs that the passengers
can read from a distance.
Moreover, CD8+ T cells are chemically attracted to the cells that might activate
them by the chemokines these other cells produce. Dr. Germain and his colleagues
demonstrated that when CD8+ T cells enter the lymph nodes and detect a potential
infection, they express receptors that allow them to detect and follow these
The NIAID team also showed that when dendritic cells interact in specific fashion
with helper T cells, the activated cell pair releases the chemokines CCL3 and
CCL4. It is the combination of these two chemokines that the CD8+ T cells receive
best as a signal, says Dr. Germain. By interfering with the action of these chemokines,
he and his colleagues demonstrated that CD8+ T cells lost their ability to home
in on the dendritic cells interacting with the helper T cells. The result was
a marked impairment of memory cell generation.
These new findings not only provide insight into the fundamental behavior of
the immune system, but also suggest that attention needs to be paid to chemokines
and chemokine receptor function when designing new vaccine strategies and evaluating
whether drugs targeting chemokines might have unanticipated effects on immune
To see a video clip of CD8+ T cells moving through the lymph nodes of a live
mouse that has been vaccinated, visit http://www3.niaid.nih.gov/news/newsreleases/2006/CD8T_vid.htm.
News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.
NIAID is a component of the National Institutes of Health. NIAID supports
basic and applied research to prevent, diagnose and treat infectious diseases
such as HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also supports
research on basic immunology, transplantation and immune-related disorders,
including autoimmune diseases, asthma and allergies.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.