Diabetes mellitus is characterized by chronic hyperglycemia caused by a deficiency in insulin action, insulin secretion or both. Type 1 diabetes is classified as the destruction of beta cells leading to a deficiency in insulin production. Type1 diabetes accounts for 5-10% of patients with diabetes and most commonly is caused by the autoimmune destruction of the beta cells in the pancreas. The adaptive immune system is composed of antigen specific T and B lymphocytes which play a central role in protecting the human body from infectious pathogens but occasionally autoreactive T and B cells can escape immune tolerance, become activated and induce autoimmune diseases. Naïve T cells require two distinct signals one delivered via the antigen receptor and the second through the costimulatory receptor CD28 that leads to the induction of IL-2 gene transcription. IL-2 is an important T cell growth factor that can influence both immunity and tolerance. Given its pivotal role it is not surprising that the immune system places strict regulation over Il2 gene transcription that is controlled by a number of E3 ubiquitin ligases that modulate TCR and CD28 signaling. This review will examine how different E3 ligases function to control T effector cell differentiation and how studies in gene knockout animal models has been crucial in understandinghow these proteins function in vivo to regulate immune tolerance in the peripheral circulation.