Scientists pinpoint immune-system targets in complex pathogens

Our immune cells have an amazingly intricate recognition system to detect invading pathogens. Often, the intricacies have overwhelmed scientists who want to know exactly what gives an alarm signal to T cells, a class of white blood cells that recognizes invaders.

"For some pathogens like the flu, the components that trigger a host immune response have been known for quite some time," says Whitehead Member Hidde Ploegh. "But for other pathogens and viruses it's much less clear. This is especially true for the parasite Toxoplasma gondii."

Enhancing a recently developed targeting technology, researchers in Ploegh's lab now have identified two specific "epitopes" that T cells recognize before unleashing the immune system's killing machinery. (An epitope is the part of an invading molecule of the pathogen that is detected by the immune system.) Working with cells of infected mice, the scientists found that one epitope alerts T cells about a Toxoplasma infection that has just kicked off and the other epitope signals that the infection has reached a chronic stage.

"For some pathogens like the flu, the components that trigger a host immune response have been known for quite some time," says Whitehead Member Hidde Ploegh. "But for other pathogens and viruses it's much less clear. This is especially true for the parasite Toxoplasma gondii."

"Even though this parasite has been studied for many years, we didn't know how this particular set of T cells recognizes the infected cell," says Eva Frickel, a postdoctoral fellow in Ploegh's lab. She is a lead author of a paper reporting the results published in the December issue of the Journal of Infectious Diseases.

By some estimates, Toxoplasma gondii can be found in 30% of the U.S. population, typically in chronic form. The parasite sets up residency within cells, virtually invisible to the immune system. It can generate a potentially serious disease called toxoplasmosis, which wreaks havoc on immune-compromised individuals. If contracted by a pregnant woman, the infection may affect the developing fetus, causing complications including loss of vision later in life and mental retardation.

Separately, Ploegh lab scientists employed the technology to pinpoint 19 new epitopes for a natural form of the herpes virus in mice, the murine gamma herpes virus, which is similar to the human virus that causes infectious mononucleosis.

This work helps to outline the elaborate interaction between the virus and the immune system, which appears to be far quicker and broader than had been expected. The findings were reported in the December issue of the Journal of Virology. Former postdoctoral scientists within the Ploegh lab who contributed to the paper include Sara Gredmark-Russ, Evelyn Cheung, Marisa Isaacson, and Gijsbert Grotenbreg.

Originally developed by former Whitehead postdoctoral researcher Ton Schumacher, the target-seeking technology exploits the normal immune-reaction process. At the start of that process, cells continually chop up intracellular proteins into tiny peptide chunks. These fragments are shuttled to the cell surface, where major histocompatibility complex (MHC) proteins present them to roving T cells, which abound in enormous variety.

The T cells sift through the shredded proteins on the cell surface, looking for foreign invaders (the epitopes). Each T cell can bind only to one particular peptide-MHC combination. When T cells find and bind complexes that hold epitopes, they trigger the immune system's killing machinery.

The targeting technology, explains Ploegh, "uses these MHC molecules as bait to fish for T cells."

Previously, genomic knowledge about the pathogen had allowed researchers to predict a large set of its most likely epitopes. The scientists in the Ploegh lab took this information and synthesized MHC molecules that each incorporated one kind of epitope from the pathogen. These MHC molecules then could be screened in high volume against T cells from mice infected with the pathogen, to identify the epitopes playing dominant roles.

This approach can cut through the bewildering avalanche of immune responses to focus on the key mechanisms. "With this knowledge, it will be possible to approach vaccine strategies in a much more informed manner," says Ploegh.

Written by Cristin Carr.