The complex task of launching a well-organized, effective immune system attack on specific targets is thrown into high gear when either of two specific enzymes chop a protein called LAG-3 off the immune cells leading that battle, according to investigators at St. Jude Children's Research Hospital.
These cells, called T lymphocytes, are key to the body’s ability to fight off infections, tailoring the immune response so it focuses on specific targets. When activated, certain T lymphocytes called effector T cells reproduce, increasing their numbers and enhancing their ability to protect the body.
The St. Jude finding is important because it represents a new concept in how T cells are regulated, according to Dario Vignali, Ph.D., associate member of the St. Jude Department of Immunology. The study offers the first example of a protein that is required for dampening T cell activity being controlled by getting chopped off at the T cell’s surface. Certain drugs that inhibit metalloproteases now under development as treatments for multiple sclerosis and arthritis appear to work by keeping T cells on a tight leash, Vignali noted. The new discovery could demonstrate an additional way in which these drugs work. Vignali is senior author of a report on this work that appears in the January 24 issue of The EMBO Journal.
The investigators performed their studies using animal cells that were genetically modified to carry LAG-3 on their surface; the researchers also used drugs that inhibit enzymes that chop off LAG-3. The team demonstrated that the two enzymes that cleave LAG-3 are controlled by of distinct but overlapping signals generated from the T cell receptor, a specialized protein that allows T lymphocytes to “see” the outside world. The investigators showed that the T cell receptor generates a different, specific signal to control the activity of these metalloprotease enzymes, called ADAM10 and ADAM17.
Specifically, the team demonstrated that ADAM10 normally cleaves LAG-3 even before the T cells are activated. After the T cell receptor receives signals from the immune system, it causes the gene for ADAM10 to make much more of this enzyme, substantially increasing the rate of LAG-3 cleavage. However, ADAM17 is inactive until the T cell receptor triggers a molecule called protein kinase C theta to activate this enzyme. In either case, when metalloproteases remove LAG-3, the brakes are taken off T cell activity.
“Appropriate control of T cell expansion during an immune response is critical,” Vignali said. “We have uncovered a new paradigm in which specialized cell surface enzymes control this process by modulating the expression of a molecule, LAG-3, that acts as an immunological molecular brake. In turn, this process is controlled by the strength of the T cell receptor signal—the immunological ‘accelerator.’ So the more the T cell ‘accelerates,’ the more the ‘brake’ is released.”
The St. Jude team previously reported that regulatory T cells, which prevent effector T cells from running out of control and causing damage to the body, use LAG-3 to rein in these activated effector T cells (http://www.stjude.org/media/0,2561,453_5297_16097,00.html). The current study in EMBO extends that finding by showing that cleavage of LAG-3 proteins on the surface of T cells allows them to greatly increase their proliferation rate during such a battle. The team also showed that cleaved pieces of LAG-3 do not contribute to T cell control, but are rather “waste” products that are swept away later.
The other authors of the paper include Nianyu Li (formerly at St. Jude; now at Amgen Inc., Thousand Oaks, Calif.), Yao Wang, Karen Forbes, Kate Vignali and Creg J. Workman (St. Jude); Bret S. Heale and John J. Rossi (Beckman Research Institute of the City of Hope, Duarte, Calif.); Paul Saftig (Christian-Albrechts University, Kiel, Germany); Dieter Hartmann (Leuven and Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium); Roy Black (Amgen Inc.; Seattle); Carl P. Blobel (Weill Medical College of Cornell University, New York); and Peter J. Dempsey (University of Washington, Seattle).
This work was supported in part by the National Institutes of Health, a Cancer Center Support CORE grant, ALSAC and the German Research Foundation.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.
Journal
The EMBO Journal