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    Dario A. A. Vignali, PhD

    Dario A. A. Vignali, PhD

    Chopping off protein puts immune cells into high gear

    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 chops a protein called LAG-3 off the immune cells leading that battle, according to St. Jude investigators. The immune cells, called T lymphocytes, are key to the body’s ability to fight off infections, tailoring the immune response so that 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, PhD, 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. Vignali is senior author of a report on this work, which appears in the January 24 issue of The EMBO Journal.

    The team demonstrated that LAG-3 is cleaved by two metalloprotease enzymes, called ADAM10 and ADAM17. The activity of these enzymes is controlled by distinct but overlapping signals generated by the T cell receptor, a specialized protein that allows T lymphocytes to “see” the outside world. When metalloproteases remove LAG-3, the brakes are taken off T cell activity. Moreover, certain metalloprotease inhibitors now under development as treatments for multiple sclerosis and arthritis appear to work by keeping T cells on a tight leash. So the new discovery could represent an additional way in which these drugs work.

    “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. This process is in turn 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.”

    Other authors of the paper include Immunology employees Karen Forbes, Kate Vignali, Yao Wang and Creg Workman, PhD, and former St. Jude employee Nianyu Li.

    February 2007