Tufts University School of Medicine researchers have identified how cell-surface receptors cooperate to generate immune responses in a process referred to as costimulation. They formulated a fluorescent imaging technique that reveals the dynamic movements of proteins within living T cells, explains Stephen Bunnell, Ph.D., assistant professor of pathology.
T cells, which mount a defense against pathogens, are much more likely to identify these organisms when integrins, which are a group of cell-surface receptors, become involved. In previous research, integrins and antigen receptors were thought of as working individually.
Earlier studies by Dr. Bunnell and other investigators, have led researchers to believe that antigen receptors are most effective when located near integrins. This study indicates that integrins influence the transmission of signals through the same complexes used by the T-cell antigen receptor.
First author, Ken Nguyen, a graduate student in immunology in Dr. 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 reportedly first discovered by Dr. 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,” Dr. Bunnell explains. “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.”
In activated T cells, many actin filaments grow at one end and fall apart at the other, flowing away from the growing end. 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 Dr. Bunnell.
“We have known for some time that integrin signaling and T-cell costimulation contribute to autoimmunity,” notes Naomi Rosenberg, Ph.D., vice dean for research at Tufts University School of Medicine. “Bunnell's images allow us to see that these can be related phenomena: integrins sensitize the immune system to antigens.”
The research appears in the June 13 issue of Immunity.