As CD28-B7 interaction is mandatory for Treg development and homeostasis, these results together with the data from the phase III BENEFIT study, reporting an increased occurrence of acute graft rejection episode and lymphoproliferative disorders in renal transplant patients treated with belatacept, have raised concerns about the negative impact of CD28-B7 blockade on regulatory mechanisms and graft survival (56–58). This evidence concerns the gene CD28 and lymphoproliferative syndrome.