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Chopping Off Protein Puts Immune Cells Into High Gear


St. Jude study shows LAG-3 protein on activated T lymphocytes slows replication until ADAM10 and ADAM17 enzymes cleave it off to allow these cells to reproduce rapidly

MEMPHIS, Tenn., Jan. 24 /PRNewswire/ -- 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, he said.

The team demonstrated that LAG-3 is cleaved by two metalloprotease enzymes, called ADAM10 and ADAM17. The activity of these enzymes is under controlled by distinct but overlapping signals generated from the T cell receptor, a specialized protein that allows T lymphocytes to "see" the outside world. In either case, when metalloproteases remove LAG-3, the brakes are taken off T cell activity. 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.