The discovery of a crucial mechanism that controls the activation of T cells, a blood cell whose primary job is to fight infection in the body, may enable the development of new drugs to treat autoimmune disease, transplant rejection, and similar disorders in which T cells play a major role. The finding, "T Cell Receptor Signals to NF-kB Are Transmitted by a Cytosolic p62-Bcl10-Malt1-IKK Signalosome," was published in the May 13 issue of Science Signaling.
A team of Uniformed Services University of the Health Sciences (USU) researchers led by Dr. Brian Schaefer, Associate Professor in USU’s Department of Microbiology and Immunology, has demonstrated that the “POLKADOTS signalosome” (named for its dot-like appearance in cells) activates a protein called “NF-kappaB” in T cells. A signalosome is a cluster of proteins that works together inside a cell to control the activity of other proteins. NF-kappaB is a protein that turns on many different T cell functions, including those that contribute to autoimmunity and rejection of transplants.
Dr. Schaefer’s team, including lead author, Dr. Suman Paul, had previously shown that the POLKADOTS signalosome, in addition to activating this protein, also limits how much NF-kappaB is turned on. Because the POLKADOTS signalosome is a major point of control for NF-kappaB activation, it may be an attractive target for the design of new drugs to block or regulate T cell functions.
Normally, T cells play a key role in maintaining health, by helping to eliminate invading disease-causing bacteria and viruses. However, in some individuals, T cells begin to react against tissues in the body, causing autoimmunity. Also, when a patient receives an organ transplant, T cells will react to that organ and cause transplant rejection, if T cell functions are not successfully blocked. There are currently only a small number of drugs available to treat autoimmunity and transplant rejection, and these drugs do not work for all patients.
Inhibiting NF-kappaB activation has long been recognized as a potentially useful strategy for blocking the T cell responses that cause autoimmunity and transplant rejection. However, because NF-kappaB is necessary for a wide variety of important processes throughout the body, directly targeting this protein would lead to many undesired and harmful side effects. Importantly, Dr. Schaefer’s group predicts that drugs that block the activity of the POLKADOTS signalosome would inhibit NF-kappaB only in T cells. This is because the POLKADOTS signalosome appears to be present only in T cells. If successfully produced, drugs that act on the POLKADOTS signalosome may be a powerful new therapy for the treatment of many different autoimmune diseases and transplant rejection.
This work was supported by grants from the U.S. NIH (Al057481), the Center for Neuroscience and Regenerative Medicine, and pre-doctoral fellowships from the American Heart Association (10PRE3150039) and the Henry M. Jackson Foundation for the Advancement of Military Medicine.
The Uniformed Services University of the Health Sciences, founded by an act of Congress in 1972, is the nation’s federal health sciences university and the academic heart of the Military Health System. USU students are primarily active duty uniformed officers in the Army, Navy, Air Force and Public Health Service who receive specialized education in tropical and infectious diseases, TBI and PTSD, disaster response and humanitarian assistance, global health, and acute trauma care. A large percentage of the university’s more than 5,000 physician and nearly 730 advanced practice nursing alumni are supporting operations around the world, offering their leadership and expertise. USU also has graduate programs in biomedical sciences and public health committed to excellence in research, and in oral biology. The University's research program covers a wide range of clinical and other topics important to both the military and public health. For more information about USU and its programs, visit www.usuhs.edu.
Sharon Willis | newswise
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