Immunological tolerance is actively acquired in the repertoire of CD4+ T cells by sequential checkpoints of clonal deletion and reprogramming, starting in immature T cells within the thymus and continuing during mature T cell encounters with antigens in peripheral lymphoid tissues. Here I will describe how inherited defects in ubiquitin regulating genes predispose to Type 1 diabetes and other autoimmune diseases by disrupting peripheral T cell tolerance either within responding T cells or within antigen presenting cells. NDFIP1 encodes an adapter for the ubiquitin ligase ITCH, with both NDFIP1 and ITCH inherited variants linked to human autoimmune and allergic disease. Ndfip1 is progressively induced as CD4 T cells begin dividing in response to harmless exogenous antigen or pancreatic islet-derived self-antigen, and is a critical switch forcing these cells to exit from cell cycle after 1-5 divisions in vivo before they can acquire effector functions. TNFAIP3 (A20) is also induced during lymphocyte activation, strongly associated with susceptibility to diabetes, rheumatoid arthritis and lupus, and encodes a protein with ubiquitin ligase and deubiquitinating (DUB) activity to dampen leukocyte NF-kB activation. The DUB activity itself is not critical for this function but a mutation that lessens the domain’s ability to retain its correct fold results in diabetes susceptibility, with B cells and dendritic cells intrinsically overactivated and islet-reactive CD4 cells escaping peripheral tolerance as a knock-on effect.