Novel Cellular Pathway Increases Sensitivity Of Body's Immune Detective

In the Dec. 9 issue of ScienceExpress, scientists at Rockefeller University report the discovery of a previously unknown pathway that boosts the ability of helper T cells to "motivate" killer T cells in detecting and attacking dangerous cells. The finding may help scientists to create a more effective immune response against disease and tumor formation.

Led by Christian Münz, Ph.D., the Rockefeller researchers investigated the Epstein-Barr virus (EBV), which infects over 90 percent of the adult population. Normally the immune system keeps the virus at a low profile, but Epstein-Barr can contribute to conditions such as infectious mononucleosis and such cancers as Hodgkin's disease and Burkitt's lymphoma if it escapes the controls of the immune system. One of the virus's proteins, Epstein-Barr virus nuclear antigen 1 (EBNA1), is found in all EBV-infected tumor cells and could play an important role in the tumor's detection by the immune system.

The body is protected by two branches of the immune system, the innate and the adaptive responses. The innate immune response is like the everyday police force, dealing rapidly with every kind of intruder. The adaptive immune response, on the other hand, will identify the specific threat and then tailor its attack for each unique case. The adaptive assault is coordinated by the helper T cells. In addition, cells in the adaptive immune response have memory, so repeat offenders are recognized and destroyed quickly.

Recent papers published in the journals Cell and Science by other researchers observed that because it destroys bacteria such as Mycobacterium tuberculosis that have invaded cells, the process called autophagy is important for the innate immune response. In the ScienceExpress paper, Münz and colleagues show that autophagy also assists helper T cells spot infected or cancerous cells.

"Many people have accepted the role of autophagy in innate immunity," says Münz, who is an assistant professor and head of the Laboratory of Viral Immunobiology at Rockefeller. "What our paper really does is make a bridge to adaptive immunity. At the same time that autophagy is helpful for destroying bacteria, as part of the innate immune response, it also enables the immune system to be alerted as part of the adaptive immune response."

Normally, the cell uses autophagy to destroy large, unwanted cell components such as old mitochondria, the cell's power center, or long-lived proteins or bacteria. Autophagy occurs within the cell, when a cup-shaped membrane forms and then elongates to form a closed vesicle, called an autophagosome. After fusion with lysosomes, which are vesicles containing degrading enzymes, the contents trapped inside the autophagosome are then broken apart. The pieces from inside the autophagosome help the cell "talk" with T cells.

When T cells make their rounds in the body, they communicate with cells through two types of molecules, MHC class I and II. Like identification papers, the MHC molecules show the T cell detectives small parts of proteins that "tell" the T cells whether the cell is healthy or not.

Proteins inside the cell are processed differently than proteins that come from outside the cell. "The paradigm for the longest time was that intracellular proteins are presented on MHC class I molecules," says co-first author Dorothee Schmid, a graduate student in Münz's lab. However, EBNA1 protein doesn't follow these rules. "We found that EBNA1, a protein found primarily in the nucleus, gets presented on MHC class II molecules," Schmid says.

Schmid and Casper Paludan, a visiting student in the Münz lab, discovered that pieces of EBNA1 were produced after autophagy and then picked up by MHC class II molecules.

Importantly, MHC class II molecules interact with the helper T cells, while MHC class I molecules interact with killer T cells. When helper T cells see pieces of viral or bacterial proteins on MHC class II molecules, they mobilize the rest of the immune system to destroy the dangerous cells. Without them, the immune system may still mount an attack, but it isn't nearly as effective.

"Helper T cells need to be stimulated to establish memory and to stimulate killer T cells," said Schmid. "You need both arms of immunity to get a really good response."

Münz hopes to study EBNA1 further to understand how it is targeted to autophagosomes and to MHC class II rather than class I. This knowledge could lead to more effective vaccines as well as immunotherapy for tumors.

"We speculate that other intracellular proteins follow this pathway," said Münz. "For immunization strategies, we now understand that we need to elicit good helper T cell response, but this has been difficult. If we can modify the proteins to selectively go into the autophagosome, there might be a way to get more MHC class II presentation and helper T cell activation."

Markus Landthaler, Ph.D., and Thomas Tuschl, Ph.D., from the laboratory of RNA Molecular Biology at Rockefeller University also contributed to this research. The work was funded by the Leukemia and Lymphoma society and by the New York Academy of Medicine. Dorothee Schmid was supported by a DAAD fellowship at the onset of this research.