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Cell Surface Receptors Are All “Talk”
in T Cell Stimulation
Summary
Using imaging techniques, researchers have revealed the dynamic processes that
allow receptors to communicate with one another to stimulate the immune system.
By understanding this “crosstalk” researchers expect to gain insights
into autoimmune diseases such as multiple sclerosis.
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ABOUT THE ILLUSTRATION:
Antigen
receptors (red) and their associated signaling complexes
(green) enter small clusters that are critical for T
cell activation. Here, ‘side views’ of
two T cells reveal how integrins alter movements within
these cells over time. If no binding partner for the
integrin VLA-4 is present (left), the signaling complexes
move towards the center of the T cell. In contrast,
when VLA-4 is bound (right), the signaling complexes
cannot move inwards. |
BOSTON (June 12, 2008) — Understanding the mechanisms that drive
healthy immune responses is important when it comes to combating autoimmune
diseases, which occur when cells that should attack invading organisms
turn on the body instead. In a study published in the June 13, 2008,
issue of Immunity, Tufts researcher Stephen
Bunnell, PhD, describes
how cell surface receptors cooperate to generate immune responses in
a process referred to as costimulation. To reveal how these receptors
communicate, Bunnell, assistant professor of pathology at Tufts University
School of Medicine and a member of the immunology program faculty at
the Sackler School of Graduate Biomedical Sciences, formulated a fluorescent
imaging technique that reveals the dynamic movements of proteins within
living T cells.
T cells play an essential role defending the body against viruses
and bacteria. To mount these defenses, T cells must sense these pathogens
via cell surface receptors known as antigen receptors. T cells are
much more likely to ‘see’ the invading organisms when a
second group of proteins, known as integrins, becomes involved. Integrins
are also cell surface receptors, and act as adhesive hooks that allow
the T cell to latch onto its environment. “What we are providing
here is insight into how these receptors collaborate, or ‘talk’ to
one another,” says Bunnell.
First author Ken
Nguyen, a graduate student in immunology in Bunnell’s
laboratory, found that a particular integrin, VLA-4, influences how
cellular structures known as SLP-76 microclusters move within the responding
T cell. These structures, which were first discovered by Bunnell, are
assembled by the antigen receptor and relay information that is essential
for T cell activation. “SLP-76 is a molecular building block
that is employed by both antigen receptors and integrins. When VLA-4
is not involved, SLP-76 microclusters move away from the antigen receptor,
which causes them to fall apart. We discovered that VLA-4 prevents
the separation of SLP-76 microclusters from the antigen receptor. This
keeps each SLP-76 microcluster intact for a longer time, and favors
the transmission of stimulatory signals,” says Bunnell.
Actin filaments are a major component of the ‘skeleton’ that
enables cells to move. In activated T cells, many actin filaments grow
at one end, and fall apart at the other. These actin filaments ‘flow’ away
from the growing end, much like a treadmill. Nguyen and colleagues
showed that these flows drive SLP 76 from the antigen receptor, but
are slowed when VLA-4 is engaged. “By altering the movement of
actin within the cell, the integrin is collaborating with the antigen
receptor to immobilize these complexes and make them survive over time,” says
Bunnell.
“We have known for some time that integrin signaling and T cell
costimulation contribute to autoimmunity. Bunnell’s images allow
us to see that these can be related phenomena: integrins sensitize
the immune system to antigens,” says Naomi Rosenberg, PhD, dean
of the Sackler School of Graduate Biomedical Sciences and vice dean
for research at Tufts University School of Medicine.
In previous research, integrins and antigen receptors were thought
of as working individually, in terms of geography and mechanism. Earlier
studies by Bunnell, and recent studies by other investigators, have
led researchers to believe that antigen receptors are most effective
when located near integrins. Importantly, this study indicates that
integrins influence the transmission of signals through the same complexes
used by the T cell antigen receptor.
“You need to understand the communication between the receptors
in order to intelligently intervene and enhance the response to a virus
or bacteria, or inhibit a destructive response,” says Bunnell.
Bunnell’s future research will examine how integrins alter the
mechanical properties of activated T cells. By studying how integrins
influence the SLP-76 complex, Bunnell will gain insights into the costimulatory
processes that enable normal immune responses, and go awry in autoimmune
diseases.
For more information on Bunnell’s work, please see “Understanding
the T Cell Receptor Signaling Complex.”
Nguyen K, Sylvain NR, and Bunnell SC. Immunity. 2008 (June 13);
28: 810-821. “T Cell Costimulation via the Integrin VLA-4 Inhibits
the Actin-Dependent Centralization of Signaling Microclusters Containing
the Adaptor SLP-76.” Published online June 12, 2008, doi:10.1016/j.immuni.2008.04.019 |
