"Our findings lead back to humans because they tell us about a very important mechanism for controlling autoimmunity," said Diane Mathis, a Harvard Medical School professor of medicine at Joslin. "At the same time, they may help us understand why people develop autoimmune diseases." The findings are reported in the Oct. 11 Science.
Until recently, immune cells, in particular T cells, were thought to learn their most basic lesson--attack foreign proteins but spare those that are native--in one of two places. Those with a broad mandate, namely to monitor widely expressed cellular proteins or proteins circulating in the bloodstream, were thought to be trained to distinguish self from foreign proteins while still in the thymus. Cells that recognize proteins in organs and tissues in the periphery, such as the pancreas, thyroid, and adrenals, were believed to learn the self-vs.-nonself lesson once they left the thymus. This organ was thought incapable of producing proteins made by distant organs such as the liver, brain, and pancreas.
But it appears that T cells in training may be learning the lesson while still in the thymus. Building on work of other groups, first author Mark Anderson, a research fellow in medicine at Joslin; Emily Venanzi, a Harvard Medical School graduate student in immunology; Christophe Benoist, a professor of medicine at Joslin; Mathis, and colleagues, reported that a small network of thymic cells, the medullary epithelial cells, expresses hundreds of genes usually associated with organs such as the pancreas, brain, and liver.
"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.
While novel, the mechanism is probably only one of many that the immune system uses to educate peripheral T cells about the self-vs.-foreign distinction. "It is very dangerous for the immune system to have self-reactive T cells," Anderson said. "It takes advantage of any mechanism to get rid of these cells. So there is a whole net of mechanisms."
Other main collaborators on this study were Ludger Klein from the Dana-Farber Cancer Institute and Roderick Bronson from Harvard Medical School.
Harvard Medical School has more than 5,000 full-time faculty working in eight academic departments based at the School's Boston quadrangle or in one of 47 academic departments at 17 affiliated teaching hospitals and research institutes. Those HMS affiliated institutions include Beth Israel Deaconess Medical Center, Boston VA Medical Center, Brigham and Women's Hospital, Cambridge Hospital, Center for Blood Research, Children's Hospital, Dana-Farber Cancer Institute, Harvard Pilgrim Health Care, Joslin Diabetes Center, Judge Baker Children's Center, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Massachusetts Mental Health Center, McLean Hospital, Mount Auburn Hospital, Schepens Eye Research Institute, Spaulding Rehabilitation