Protein essential for switching on T-cell response
A minor change in a cell protein impairs the ability of a key type of immune cell to marshal the body's defenses against disease, according to a study by researchers at the National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), and the Food and Drug Administration (FDA). The study appears in the June 14 issue of Science. The researchers also found that the change causes these white blood cells, known as T-cells, to multiply out of control and to attack the body's own tissues.
Specifically, the study, by Connie Sommers, Ph.D. and her colleagues, found that the protein dubbed "LAT," for short, plays a critical role in coordinating a normal immune response.
"This discovery not only provides important insight into how the immune system functions, but may also lead to a better understanding of certain cancers of the immune system," said Duane Alexander, M.D., Director of the NICHD. "This advance may also lead to insights into a variety of new therapies for autoimmune diseases-those disorders in which the immune system attacks the body's own tissues."
The immune system is made up of cells and tissues involved in recognizing and attacking foreign substances in the body. T-cells are responsible for distinguishing between molecules foreign to the body and "self" molecules --those produced by the body. When T-cells recognize a foreign substance such as a virus or bacterium, they become activated and begin the complex immune response that rids the body of the foreign invader. Before T-cells can carry out this important task, the foreign molecule must bind to a molecule known as a receptor on the T-cell's surface. This binding process is analogous to the way a key fits into a lock. In turn, the binding triggers a number of chemical reactions-called signaling pathways--within the T-cell, enabling it to react to the disease-causing substance.
Two key signaling pathways that lead to activation in all cells are the calcium pathway and the Ras pathway. The LAT (linker for activation of T- cells) protein was first identified at the NICHD in the laboratory of Lawrence E. Samelson, M. D., one of the study's co-authors. In T-cells, this protein functions by chemically linking the receptor to both the calcium and Ras downstream signaling pathways.
In the current study, the researchers mutated a specific amino acid in the LAT protein in mice. At two weeks of age, the mice with the mutated LAT protein exhibited a partial block in T-cell production. However, by four weeks of age, abnormal T-cells had rapidly expanded and the mice showed signs of autoimmune disease.
The researchers discovered that the LAT protein produced by the mutated mice, while retaining the ability to connect T-cell activating receptors to the Ras signaling pathway, could not connect the receptors to the calcium signaling pathway.
"The results of our study indicate that T-cells don't develop normally if they don't get a calcium signal," said Paul Love, M.D., Ph.D., one of the study's authors and head of the Section on Cellular and Developmental Biology at NICHD's Laboratory of Mammalian Genes and Development. "They also show that coordinating the activation of the Ras and calcium signaling pathways is essential for a normal immune response."
The study raises the possibility that some autoimmune disorders in humans may result from mutations that cause unbalanced or uncoordinated signaling in T cells.
Next, researchers plan to study the effects of mutating other amino acids in the LAT protein. They also plan to determine if some human autoimmune diseases or disorders in which T-cells duplicate faster than normal, such as certain types of lymphoma and leukemia, are caused by mutations that result in an unbalanced cell signaling response.
The NICHD is part of the National Institutes of Health, the biomedical research arm of the federal government. The Institute sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Clearinghouse, 1-800-370-2943; e-mail NICHDClearinghouse@mail.nih.gov.