Grant: Operating Grant

The immune system is vital for protecting individuals against pathogen infections and cancers. Paradoxically, the immune system is also responsible for initiating autoimmunity by attacking healthy self-tissues. T cells are white blood cells that play a critical role in both immunity and autoimmunity. Normally, T cells that are able to recognize and destroy healthy self-tissues are eliminated during their development in the thymus while useful T cells that can combat infections are released into the circulation. Humans and mice that have mutations in genes that impair the elimination of self-reactive T cells develop autoimmunity due to a lack of self-tolerance. Therefore, in order to develop treatments for autoimmunity, it is essential to understand all the mechanisms utilized during development to enforce self-tolerance within the T cell pool. Using mouse model systems, we previously determined that there are multiple ways the immune system enforces self-tolerance. These include the removal of self-reactive T cells as well as the inactivation of self-reactive T cells. We now seek to uncover the cellular and molecular mechanisms that regulate both methods of inducing T cell tolerance. This information will be valuable in devising strategies to treat autoimmunity in genetically susceptible individuals, but also has implications in organ transplantation and cancer immunotherapy.