Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway

Impact of CTLA-4 Ig versus anti-CD28 domain Abs on alloreactive T cell responses. (A) Alloreactive T cells become activated and differentiate into cytokine-secreting effector T cells (Teffs) upon TCR recognition of alloantigen. Tregs can dampen this response by CTLA-4–mediated competition for CD28 ligands (CD80 and CD86) and by secretion of anti-inflammatory cytokines IL-10 and TGF-β. (B) CTLA-4–Ig inhibits Teff function but also impairs Treg survival and suppressive capacity, whereas selective CD28 blockade better inhibits Teff accumulation and function and better maintains Treg suppressor function by preserving CTLA-4–mediated coinhibitory signals.