A20 is an immune tolerance factor that can determine islet transplantoutcomes.
Islet transplantation can restore lost glycemic control in type 1 diabetes subjects, but is restricted in its clinical application by limiting supplies of islets and the need for heavy immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-{kappa}B signalling thresholds. Here we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45 % of recipients, and >80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon regulatory T cells, was antigen-specific and grafts showed reduced expression of inflammatory factors, but increased TGF{beta} and IL-10. By analysing islets expressing an A20 coding mutation (I325N) that cripples A20s OTU ubiquitin editing domain, we found that A20 regulates intra-graft RIPK1 levels to modulate NF-{kappa}B signalling. Transplantation of I325N islets resulted in increased NF-{kappa}B signalling, graft hyper-inflammation and acute allograft rejection. Neonatal porcine islets (NPI) represent a clinical alternative islet source but are readily rejected. However, forced A20 expression reduced NPI inflammation and increased their function after transplantation. Therapeutic administration of A20 raises NF-{kappa}B signalling thresholds and promotes islet allogeneic survival. Clinically this would allow for reduced immunosuppression supporting the use of alternate islet sources.