It has been demonstrated that bi-allelic deletion of the CTLA4 gene reduced conversion of autoreactive T cells into Treg cells.31 The requirement for bi-allelic engagement by anti-CTLA4 mAbs for irAE is at least partially explained by the requirement for bi-allelic engagement of CTLA-4 in the conversion, as an increased ratio of autoreactive effector/regulatory T cells could lead to autoimmune diseases. Here, CTLA4 is linked to autoimmune disease.