Type I interferons are a powerful cytokine family that play an essential role in innate immune protection from viruses. In addition to their direct anti-viral activities, they strongly activate multiple cells of the adaptive immune system, including APC, B cells, and T cells. Interestingly, interferons are expressed in the thymus in the steady state, in the absence of infections. In this project, we propose to systematically define the role that thymic type I interferon plays in immunological self-tolerance. We hypothesize that type I interferons are critical to promote tolerance to self-epitopes that are usually only displayed during infections.
Aim 1 will determine what stimuli promote thymic medullary epithelial cells to produce IFNb.
Aim 2 will determine the consequences of IFNb expression on tolerance to conventional and inflammation induced self-antigens.
Aim 3 will determine if autoimmunity results in the absence of thymic IFNb, particularly when mice are challenged by infections.
A meaningful understanding of autoimmune disease should take into account that humans are continually exposed to multiple bacterial, viral, fungal, and parasitic infections. These may influence immune tolerance through the effect of type I interferons a major infection reaction pathway. This proposal will explore the effect of type I interferons in tolerance, and specifically study tolerance in mice with normal microbial exposure.
