Cell surface receptors are all 'talk' in T cell stimulation

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.

Source: Tufts University

Related stories:

TB Bacterium Uses Its Sugar Coat To Sweeten Its Chances Of Living In Lungs
(PhysOrg.com) -- Common strains of tuberculosis-causing bacteria have hijacked the human body’s immune response to play tricks on cells in the lungs, scientists say.
Hair on a man's head offers clues about prostate cancer
Some of the drugs given to many men during their fight against prostate cancer can actually spur some cancer cells to grow, researchers have found. The findings were published online this week in a pair of papers in the Proceedings of the National Academy of Sciences.
Common molecule notifies immune system of prostate cancer
In experiments with mice, researchers have found that the body’s immune system can use a surprisingly common molecule to recognize prostate tumors. The molecule comes from a protein found in all cells of the body; however, immune cells appear to respond to it only when it is present on the surface of cells within a tumor.
An 'attractive' man-machine interface
Researchers at Children’s Hospital Boston have developed a new “nanobiotechnology” that enables magnetic control of events at the cellular level. They describe the technology, which could lead to finely-tuned but noninvasive treatments for disease, in the January issue of Nature Nanotechnology (published online January 3).
Molecular 'trip switch' shuts down inflammatory response
Like a circuit breaker that prevents electrical wiring from overheating and bringing down the house, a tiny family of three molecules stops the immune system from mounting an out-of-control, destructive inflammatory response against invading pathogens, researchers at the Salk Institute for Biological Studies have found.
Bound to identify intruders
The first lines of defense in our immune systems are specialized mobile units that check the identity of cells to determine whether they are 'self' or 'foreign.' A team of scientists, led by Prof. Israel Pecht of the Weizmann Institute’s Immunology Department, has now revealed in fine detail how the body’s 'reconnaissance unit' continuously screens and inspects identity.
Researchers show evidence of 'memory' in cells and molecules
Research to be reported October 29 in the journal Proceedings of the National Academy of Sciences provides evidence that some molecular interactions on cell surfaces may have a “memory” that affects their future interactions. The report could lead to a re-examination of results from certain single-molecule research.
T vs. B: Re-engineered human T cells effectively target and kill cancerous B cells
Human white blood cells, engineered to recognize other malignant immune cells, could provide a novel therapy for patients with highly lethal B cell cancers such as acute lymphoblastic leukemia (ALL), according to researchers at Memorial Sloan-Kettering Cancer Center (MSKCC). By administering repeated doses of T cells designed to express an artificial receptor which recognizes human B cells, the researchers were able to eradicate cancer in 44 percent of mice bearing human ALL tumors.

News discussion:

Medicine & Health news