Binding of T cell surface CTLA4 to antigen-presenting cell (APC) surface CD80 and CD86 blocks T cell costimulation to prevent autoimmunity. The recombinant homodimeric CTLA4-Ig fusion proteins abatacept and belatacept also block costimulation, and are effective immunosuppressive therapies in autoimmune disease and organ transplant rejection. Recently we have found that cell surface CTLA4 and CTLA4-Ig therapies also directly engage the PDL1:PD1 checkpoint through a novel mechanism that reinforces T cell suppression. Based on this new mechanism we have designed and characterised novel immunomodulatory agents.