A Brigham and Women's Hospital (BWH)-led team has identified a long-sought-after partner for a key immune protein, called TIM-3 (image), that helps explain TIM-3’s two-faced role in the immune system -- sometimes dampening it, other times stimulating it. TIM-3 is T-cell immunoglobulin mucin-3. It negatively regulates Th1 responses and affects macrophage activation. This newly identified partner of TIM-3 not only sheds light on the inner workings of the immune system in diseases such as HIV, autoimmunity, and cancer, but also provides a critical path toward the development of novel treatments that target TIM-3. The research findings were publishe online on October 26, 2014 in Nature. "There has been a lot of confusion around TIM-3 -- how does it both inhibit and activate the immune system," said Dr. Richard Blumberg, chief of the Division of Gastroenterology, Hepatology, and Endoscopy at BWH and senior author of the paper. "This is a crucial question because TIM-3 has been recognized as an important drug target, but nobody really understands exactly how to approach it because of this Janus-like property." The interest in TIM-3 as a drug target stems largely from its inhibitory role, particularly in cancer. When immune cells are stimulated over long periods of time, they switch on signals, such as TIM-3, that help them dial down their own activity. This chronically activated state, termed "exhaustion," is an immunological hallmark of chronic viral infections, such as HIV. It is also common in cancer. If there were a way to block TIM-3 pharmacologically, it could unleash the immune system, freeing it to attack tumors. Despite this interest, the details of how TIM-3 works have been unclear -- until now. Dr.
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