Shadow proteins in thymus - Clues to how immune sys...( munology; Christophe Benoist a profess...)

"No one would think you would encounter your big toe protein in the thymus, but in fact proteins from the eye, the liver, from all over the place are specifically expressed in a small population of stromal cells in the thymus," said Benoist.

A majority of these expressed proteins are used by the peripheral organs to tell T cells to stay away. Indeed, the researchers believe the proteins are used in the thymus to foreshadow the very self-antigens that the T cells will encounter once they travel out into the body. "There is a foretelling of these proteins in the thymus, which is why we call it an immunological self-shadow," said Mathis.

In a critical step, the Joslin team discovered that the transcription factor aire plays a critical role in producing these self-shadow proteins in the thymus (hence its name, which is formed from two letters in each word of autoimmune regulator). Mutant mice lacking aire exhibited in their thymus only a fraction of the peripheral self-proteins found in the thymus of normal mice. And the mutants exhibited widespread autoimmunity. In fact, their condition was reminiscent of a condition found in humans carrying a defective AIRE gene, autoimmune polyglandular syndrome.

It is not yet clear how the shadow proteins educate developing T cells inside the thymus, though Benoist suspects the processes are similar to those used to eliminate T cells that react to ubiquitous or circulating proteins. Nor is it clear how aire controls the expression of so many shadow proteins. One possibility is that it works by binding to other transcription factors. "It is going to be interesting to figure out what the mechanism really is," she said.

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Contact: Marge Dwyer
Marjorie.Dwyer@joslin.harvard.edu
617-732-2415
Harvard Medical School
10-Oct-2002