ARLINGTON, Va., April 26, 2005 -- Darrell Irvine, Ph.D., of the Massachusetts Institute of Technology is conducting basic studies on the molecular steps necessary for the human immune system to launch an attach against a foreign invader.

Irvine, assistant professor of biomedical and biological engineering, has the short-term goal of better understanding the complexity of the immune system. His long-range objective is to use this understanding to strengthen a weak immune response or to help the immune system launch an attack against a specific target, such as cancer cells.

One area of his research focuses on the signaling that occurs between two cell types of the immune system-T cells and antigen-presenting cells. T cells play a central role in launching an immune response and in fighting disease-causing invaders.

Antigen-presenting cells roam the body looking for cells that might pose a threat. They digest dying cells and pathogens and present pieces of them to T cells for inspection. These pieces of protein, toxin, bacteria and the like are called antigens.

In an exchange between T cells and antigen-presenting cells, a decision is made. Is there a threat calling for a counterattack? If so, the T cell is responsible for setting the immune response into motion. This is a tightly controlled process because it must result in an effective counterattack against invading pathogens and at the same time protect healthy tissue and guard against an autoimmune response.

The initial exchange between a T cell and an antigen-presenting cell occurs at the point where the two come together. As the two cells approach each other, a synapse is formed. The synapse has a physical structure resembling a scaffold, which helps hold the two cells together so they can exchange information. The synapse is also thought to play a role in communication between the two cells. Irvine wants to understand synapse formation and what role the synapse itself plays in the immune response.

To investigate this process, he has developed artificial surfaces that display proteins just as antigen-presenting cells do. He can change the arrangement of these proteins to see what effect the changes have on T cell response.

The key to this line of research is the ability to control the assembly of multiple different proteins on an artificial surface. The conventional ways researchers lay out proteins on a surface include soft lithography and photolithography, both of which can erode or destroy protein function.

Irvine and his collaborators have developed a unique surface on which they can immobilize multiple proteins in desired patterns at the nanometer scale and fix them to the surface without degrading their function.

"This technology allows, for the first time, multiple fragile proteins to be assembled on surfaces with the resolutions achieved in photolithography," Irvine said. "These surfaces hold significant promise as tools for studying cell-cell interactions in the laboratory by engineering surrogates of live cells."

Irvine's group is also exploring how the physical structure of the synapse and the physical distribution of its components determine the signals that are passed on to the T cell. There is some evidence that the physical structure and how it is assembled play a role in stimulating a T cell to launch an immune response.

Knowledge gained through these and other experiments can be used to stimulate a particular immune response or to strengthen a weak one. An example of this approach might be to take blood from a cancer patient, isolate T cells from it, and then stimulate these cells to reproduce and multiply into a much larger cell culture. Surrogate antigen-presenting cells could then be used to present the T cells with antigens from the cancer cells. This would activate the T cells to recognize and fight these specific cancer cells. The T cell population would then be returned to the patient to battle the tumor.

"It might be possible to have cell culture dishes with fabricated surfaces designed to present antigens to T cells. You would seed T cells from a patient's blood on the surface; the surface itself would then select and expand the activated T cells. These activated T cells would be returned to the patient," Irvine said.

One of Irvine's most significant findings so far is confirmation that the physical distribution of signal receptors can make a big difference in the strength of signaling between the T cell and the antigen-presenting cell. If the receptors are distributed in nanometer-scale clusters, the signals between the two cells are much stronger.

"The strength of the signal change has surprised us," Irvine said. "Now we're trying to determine how much this might affect the overall immune response."

Irvine received a Whitaker Foundation Biomedical Engineering Research Grant in 2003 for a study of T cell activation in lymph nodes.

Contact:
Darrell Irvine, Massachusetts Institute of Technology
Frank Blanchard, The Whitaker Foundation