A protein called TRAF3, with a previously unknown job in immune cells, is actually a key part of a mechanism that triggers release of anti-virus molecules called type I interferons (IFNs) as part of the body's rapid response against these invaders, according to investigators that include a scientist continuing this work at St. Jude Children's Research Hospital.
The discovery of TRAF3's role helps to explain how immune cells called macrophages use sensing devices called Toll-like receptors (TLRs) to orchestrate just the right response to different types of infections. TLRs are on the outer membranes of macrophages and respond to germs by triggering the production of proteins called cytokines. Various cytokines regulate different biological functions that are important during immune responses, such as inflammation and protection against viruses. In addition, some cytokines contain anti-inflammatory activities, which curb potentially harmful inflammation.
The researchers showed that TRAF3 is not only essential for production of type I interferons, but also for production of IL-10, a protein that prevents inflammation. In fact, the team showed that cells lacking the gene for TRAF3 can't produce IL-10 and instead over-produce proteins that cause inflammation.
A report on these results appears online in the November 23 prepublication issue of Nature.
"The discovery that TRAF3 is also recruited to Toll-like receptors was important," says Hans Haecker, M.D., Ph.D., the first author of the paper and currently an assistant member of the St. Jude Department of Infectious Diseases. "It filled in an important piece of the puzzle of the front-line immune response to viruses that we didn't even realize was missing. Further research using this simple system will help solve the mystery of how macrophages can pick and choose among different strategies for combating specific infections." Haecker was at the Technical University of Munich and the University of California, San Diego, when he worked on this project.
Researchers already knew that TLRs use proteins called adapters to help them recruit small armies of signaling molecules that trigger the right response by the immune cell to invaders, such as viruses. They also knew that a protein called MyD88 was one of the adaptors that help to recruit these armies; and that one of the first proteins in the signaling army recruited to MyD88 was the protein TRAF6. But what was unclear was the exact series of steps that occurred during the recruitment of the full army of signaling molecules by TLRs.
Therefore, the team developed a novel strategy to study how TLRs recruit their armies of signaling molecules. The team inserted into macrophages an artificial gene that coded for the TLR adaptor MyD88 fused to a molecule called gyrase B. In the presence of a drug called coumermycin, gyrase B, these molecules bind together in pairs. This 'pair forming' activity of gyrase B triggered a similar formation of pairs of the MyD88 molecules that were fused to gyrase B. This reaction, which produced pairs of MyD88-gyrase B complexes, then triggers recruitment of the rest of the army of proteins that form the macrophages's signaling pathway, according to Haecker.
During these studies the researchers discovered that TRAF3 as well as TRAF6 is recruited to such adaptors. In addition to demonstrating that TRAF3 was recruited by MyD88 to generate type I interferons, the researchers showed that TRAF3 can be recruited by another important adaptor, called TRIF, which is used by some TLRs. This demonstrated that TRAF3 has a general role in controlling the TLR-dependent type I interferon and IL-10 response.
Results of the study suggest that the specific type of immune response triggered by TLR signaling depends on the relative amounts of TRAF6 and TRAF3 initially recruited, and the different signaling proteins each of those proteins subsequently recruit to the growing army.
The TLR system is part of the body's innate immune response. Innate immunity is a primitive type of defense that does not use antibodies. Instead, immune cells that are part of innate immunity act as an early-warning system that attempts to stop infections quickly so that the other, more complex immune responses don't have to be called into play.
Other authors of the study include Vanessa Redecke, Li-Chung Hsu, Gang G. Wang, Mark P. Kamps, Eyal Raz and Michael Karin (University of California, San Diego); Blagoy Blagoev, Irina Kratchmarova and Matthias Mann (University of Southern Denmark); Hermann Wagner and Georg Haecker (Technische Universität München, Munich, Germany).
This work was supported in part by the National Institutes of Health, the American Cancer Society and the Deutsche Forschungsgemeinschaft.
St. Jude Children's Research Hospital
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