Investigators Find Way to Increase Number and Function of Regulatory T Cells
12/21/2007Overactive immune responses, sometimes referred to as autoimmune diseases, occur when the body's immune system fails to recognize its tissues and cells, and attacks them as harmful foreign agents. A subset of immune cells, called regulatory T cells or Treg cells, suppresses activation of the immune system and closes down immune responses that could potentially attack the body's own tissues.
A protein called Foxp3 is a key component of Treg cells; it regulates their development and function, and serves as a cellular marker. Children's Hospital investigators have discovered a way to increase the gene expression of Foxp3, increase the number of immune suppressing Treg cells that express Foxp3, and enhance the suppressive function of these cells in vitro and in vivo.
Investigators led by Wayne W. Hancock, M.D., Ph.D., Division of Transplantation Immunology, examined optimal Treg function and found that Foxp3 is regulated by acetylation of several lysines in the forkhead domain of Foxp3 that were not previously thought to be involved in Foxp3 function. In addition, the investigators found that Foxp3 acetylation enhanced binding of Foxp3 to the promoter for interleukin 2 (IL-2), and suppressed IL-2 production, an essential activity of Treg.
"We found that the key component of Tregs that people recognize, namely Foxp3, has to be activated for the Tregs to function," says Dr. Hancock. "We used inhibitor molecules to present this aspect of biology in a new way, and show the impact of altering the function of Tregs in autoimmune disorders."
These results, published recently in Nature Medicine, elucidate previously uncharacterized and therapeutically relevant mechanisms to alter inflammatory and immune responses in vivo. They may lead to a way to pharmacologically enhance the suppressive properties of naturally occurring Treg cells. Ultimately, therapies that improve the body's own cell population production may complement or replace therapies that depend on cellular transfer of Tregs.
Dr. Hancock's Hospital co-authors include Ran Tao, M.D., Engin Ozkaynak, Ph.D., Chunxia Chen, Ph.D., Liqing Wang, M.D., Ph.D., and Andrew Wells, Ph.D., Division of Transplant Immunology, and Edwin de Zoeten, M.D., Ph.D., Division of Gastroenterology, Hepatology and Nutrition. The National Institutes of Health provided support for this study.