E3 ubiquitin ligases and their control of T cell autoreactivity

Autoreactive T cells are involved in the development of most autoimmune diseases. Consequently, the induction and maintenance of T cell tolerance to self-antigens is as important to the normal function of the immune system as is the activation of T cells in the presence of pathogens. Despite the enormous effort that has already been made to understand the biochemical and cellular mechanisms that lead to the development of immune tolerance in model systems, we do not yet understand how to re-institute immune self tolerance in individuals that have already developed autoimmune disease. Therefore, a better understanding of the molecular processes involved in this immunological decision-making offers the possibility of defining new therapeutic targets and designing new agents that can better promote a state of immunological self tolerance and more effectively treat clinical autoimmunity.In this review, we will discuss a novel form of T cell regulation that involves a post-translational modification of proteins by ubiquitination. This system of protein ubiquitination plays a key role in many cellular processes, such as the regulation of the cell cycle, modulation of cell surface receptors, cellular differentiation, DNA repair, gene transcription, and cellular stress responses. In the innate immune system, ubiquitin-dependent proteasomal degradation of foreign proteins mediates antigen presentation. Furthermore, the activation of the proinflammatory cytokine gene transactivator nuclear factor κB (NFκB) relies on ubiquitin-mediated degradation of the IκBα inhibitory protein at sites of infection and/or inflammation. Recently, protein ubiquitination has been shown to mediate several important molecular functions in T cells that are linked to the avoidance or development of autoimmunity. Below, enzymes important to the regulation of protein ubiquitination in T cells will be described and their roles as negative regulators of autoimmunity will be considered in more detail.Ubi