Cytotoxic T lymphocytes are immune cells that normally protect the body from infection by destroying cancer cells and cells infected with dangerous bacteria or viruses. However, overactivation of T cells can lead to an assault on the body's own healthy tissues, leading to some form of autoimmune disease. The protein cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is well known as an important regulator of the immune system and plays a critical role in down-regulating T cell responses.
Dr. Linda S. Wicker from the Cambridge Institute for Medical Research and Dr. Vijay K. Kuchroo from the Center for Neurologic Diseases at Brigham and Women's Hospital and Harvard Medical School examined the function of a newly discovered naturally occurring form of CTLA-4 called ligand independent CTLA-4 (liCTLA-4) because low levels of this alternate form of CTLA-4 have been associated with autoimmune disease susceptibility.
The researchers found that liCTLA-4 is present in T cells and vigorously inhibits T cell responses. There was an enhanced expression of liCTLA-4 protein in the T cells of a special strain of mice that is resistant to type 1 diabetes compared to a strain of the mice that is susceptible to the disease.
The researchers conclude that increased expression of liCTLA-4 reduces activation of T cells and thus plays a role in preventing susceptibility to T cell-mediated autoimmune diseases. "The discovery of a new form of CTLA-4 was a completely unexpected result and demonstrates that the study of natural variation of genes altering autoimmune diseases such as type 1 diabetes can yield new insights even about molecules that have already been the subject of extensive study, such as CTLA-4," explains Dr. Wicker. According to Dr. Kuchroo, "This taught us that in many cases the disease may not be due to big changes in the affected genes but instead due to subtle differences in the amount of alternate forms of the gene that are expressed."
Lalitha Vijayakrishnan, Jacqueline M. Slavik, Zsolt Illés, Rebecca J. Greenwald, Dan Rainbow, Bernhard Greve, Laurence B. Peterson, David A. Hafler, Gordon J. Freeman, Arlene H. Sharpe, Linda S. Wicker, and Vijay K. Kuchroo Autoimmune Disease-Associated CTLA-4 Splice Variant Lacking the B7 Binding Domain Signals Negatively in T Cells.
Published in Immunity, Volume 20, Number 5, May 2004, pages 563-565.