Modes of action of Abatacept/Belatacept and anti-CD28 domain antibodies. (A) During a normal immune response, both conventional T effector cells (Teff) and T regulatory cells (Treg) receive a primary activation signal via TCR engagement with peptide/MHC complexes presented on antigen presenting cells (APCs). To become fully activated, a second, co-stimulatory signal is also required, shown here as CD28 on the surface of T cells binding its ligand CD80/86. CTLA-4 is also capable of binding CD80/86, resulting in coinhibition of T cells. In addition, CTLA-4 expression on Tregs is important for their function. (B) Treatment with Abatacept/Belatacept blocks the shared ligands for CD28 and CTLA-4, thus blocking CTLA-4 mediated coinhibitory signals that serve to dampen effector T cell responses and promote Treg-mediated suppression. (C) Anti-CD28 domain antibodies selectively target CD28, while leaving CTLA-4 intact.