E3 ubiquitin ligases as T cell anergy factors

E3 ubliquitin ligases have emerged as key molecular regulators of immune cell function. Three families of proteins with ubiquitin ligase activity have been described (the HECT, RING and U-box proteins), and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation. This review will discuss the relationship between the ubiquitination of select components of the antigen-sensing signaling apparatus in T cells and the development and maintenance of the clonal anergy state.