Cell surface receptors coordinate to generate immune Responses

Washington, June 13 : In a new study, researchers at Tufts University School of Medicine have described how cell surface receptors work in tandem to generate immune responses in a process referred to as Co-stimulation.

Co-stimulation is often crucial to the development of an effective immune response, and understanding this is important when it comes to combating autoimmune diseases, which occur when cells that should attack invading organisms turn on the body instead.

In order to reveal how these receptors communicate Stephen Bunnell, PhD, assistant professor of pathology at Tufts formulated a fluorescent imaging technique that reveals the dynamic movements of proteins within living T cells.

T cells play an important role in 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," said Bunnell.

The researchers found that a particular integrin, VLA-4, controls how cellular structures known as SLP-76 microclusters move within the responding T cell. These structures are assembled by the antigen receptor and pass on information 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," said 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. Researchers 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," said Bunnell.

Earlier, integrins and antigen receptors were believed to be 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," said Bunnell.

The study is published in the latest issue of Immunity.

ANI