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.
Contact: Susan Marsiglia or Bob Bock
NIH/National Institute of Child Health and Human Development