Signalling of E3 ubiquitin-protein ligases in the regulation of priming and tolerance of T cells

An effective immune system is essential for constant surveillance of potential threats to the organism, its’ primary role being to provide resistance to infection. Thus, the immune system must be able to discriminate between pathogenic and self or harmless foreign antigens in order to not only achieve a productive immune response but also to avert unwarranted hyperreactivity and the potential development of autoimmunity. A delicate balance between these two fundamental requirements of the immune system must therefore exist. T cells take central roles in the orchestration of the immune response. They are responsible for adaptive cell-mediated immunity and as such they can eliminate infected cells, produce cytokines that help in the resolution of the infection, stimulate other cells of the immune system to participate in the immune response and turn into long-lived memory cells. It is not surprising then that a wealth of mechanisms exist in order to ensure that T cells mediate immunity against pathogenic antigens but not to self or harmless ones. Indeed, various checkpoints in T cell development exist in the thymus to enable, on the one hand a large pool of diverse and functional T cells capable of recognising virtually all antigens while, on the other hand, eliminating self-reactive T cells. As some self-reactive T cells manage to leave the thymus, additional mechanisms have evolved to continually protect against auto-reactive and allergic inflammatory responses in the periphery. These mechanisms of peripheral tolerance include cell-mediated suppression of T cell responses, T cell apoptosis and T cell anergy. Anergy is a long-lived, cell-intrinsic mechanism that is characterised by cell cycle progression arrest and reduced IL-2 production. While T cell priming requires recognition of the cognate antigen in the context of MHC and co-stimulation via the interaction of its CD28 receptor with CD80/86 on an APC, recognition of the cognate antigen in the context of MHC wit