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St. Jude Study Shows How T Cell's Machinery Dials Down Autoimmunity
Date:5/12/2008

ITAMs are components of the CD3 adaptor proteins that attach to the T cell receptor and help transmit the control signals from the T cell receptor into the cell.

"The ITAMs we studied are little molecular tags inside the cell by which the T cell receptor communicates to the rest of the cell," Vignali said. "The mystery we wanted to address was why the T cell receptor needs 10 ITAMs to do its job. Why not just have a simple on/off switch?"

To explore the role of multiple ITAMs, Jeff Holst, Ph.D., the paper's first author and a St. Jude postdoctoral scientist, used a technique developed in the Vignali lab to produce mice whose T cells have variations in the number and type of functional ITAMs. The technique involved using a virus as a genetic cargo-carrier to transport genes for different combinations of normal and mutant non-functional ITAMs into the mouse cells.

The researchers found that reducing the number of normal ITAMs caused the mice to develop autoimmune disease. However, the investigators also found that some mice with fewer than normal functional ITAMs did not become sick with autoimmune disease. Vignali said this finding suggests that it is not just the number of ITAMs, but also their type that may influence T cell function.

"We theorized that there were two possibilities why the immune system needs so many ITAMs," he said. "One is that the requirement was purely quantitative, and that the ITAMs were there for signal amplification. The second possibility is that different ITAMs do slightly different things -- they do have slightly different structures, so maybe they bind to some signaling molecules better than others; and their positions in the T cell receptor are different. So, while our primary observation is that quantity is more important than ITAM type, we also found that type has some influence."

The researchers' analyses of the immune systems of the altered mice indicated that reducing the number of norm
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SOURCE St. Jude Children's Research Hospital
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