"Now that we know that some T cells need to see these types of modifications to identify an invader, we can see if incorporating such changes into the proteins is helpful for vaccination," says senior author Emil R. Unanue, M.D., the Edward Mallinckrodt Professor and head of Pathology and Immunology.
The finding may also be relevant to autoimmune conditions where the immune system erroneously attacks healthy tissues. Such disorders include rheumatoid arthritis, multiple sclerosis and type 1 diabetes.
"We show in this study that during some infections, these same types of modifications can be made to our own proteins, potentially leading to T cell attacks on the self," says Unanue.
Unanue and colleagues, who publish their results on May 31 in the Proceedings of the National Academy of the Sciences, conducted their studies in mice and in cultures of mouse cells. Jeremy Herzog, a research associate in Unanue's lab, did many of the experiments and was the lead author of the study.
T cells belong to a class of immune cells known as thymic-lymphocytes, which in turn are a component of the branch of the immune system known as adaptive immunity. This branch responds to pathogens after they interact with the other major branch, the innate immune system. T cells kill pathogens or produce molecules like cytokines that stop their growth.
Scientists have known for some time that a second class of innate immune system cells known as antigen-presenting cells helps T cells determine what to attack. They do this by displaying fragments of proteins they have picked up on their surfaces f or inspection by T cells. Fragments of proteins are called peptides.
Researchers also knew that when antigen-presenting cells are activated by inflammatory factors or microbial products, they start putting out chemically unstable compounds such as nitric oxide and superoxide. Together, these compounds generate peroynitrate, a highly potent chemical that modifies many proteins.
Unanue's group showed that this chemical modifies the peptides presented by antigen-presenting cells in several distinct ways. For example, they attach a nitrate group to the amino acid tyrosine in the peptides, changing it to nitrotyrosine.
Unanue's lab then showed that these changes increased the chances that various types of T cells would react to the modified peptides shown to them by antigen-presenting cells.
Unanue's group is working to substantiate their findings and explore their potential relevance to different areas of biomedical research. He notes that insulin-producing beta cells, the pancreatic cells attacked by T cells in type 1 diabetes, also generate reactive compounds similar to those made by antigen-presenting cells.
"The beta cells could therefore be modifying their own proteins in the same way that antigen-presenting cells are modifying foreign proteins," he says. "We're now investigating whether such modifications can cause T cells to attack the beta cells."
Damaging oxidative reactions are also believed to play a role in atherosclerosis. Scientists suspect oxidative damage in the blood vessel walls may lead to immune reactivity that contributes to narrowing and stiffening of blood vessels.
Herzog J, Maekawa Y, Cirrito TP, Illian BS, Unanue ER. Activated antigen-presenting cells select and present chemically modified peptides recognized by unique CD4 T cells. Proceedings of the National Academy of the Sciences, 102 (22), 7928-7933.
Funding from the National Institutes of Health and the Kilo Diabete s and Vascular Research Foundation supported this research.