[Regulation of T-cell activation by CD28 and CTLA-4]

T CELL RESPONSE: T lymphocytes play a key role in the coordination of the immune response. T helper cells contribute primarily by means of cytokine release, whereas cytotoxic T cells eliminate cells bearing antigens recognized as foreign. Through its T cell receptor each T cell can recognize a specific peptide antigen, which is presented in the context of the major histocompatibility complex (MHC) to T helper cells by specialized antigen-presenting cells or to cytotoxic T cells by nearly all body cells. Upon contact with its specific antigen, the T cell receptor transduces an activation signal into the T cell, leading to proliferation, cytokine production, or efficient cytotoxicity.

However, a second costimulatory signal is necessary to achieve complete activation. This can be provided by the accessory T cell molecule CD28 upon binding to its respective ligands B7-1 (CD80) or B7-2 (CD86). The same ligands bind to CTLA-4 (CD152), a receptor expressed at the surface of T cells previously activated for 2 to 3 days and capable of downregulating activation. IMMUNOSUPPRESSION BY CTLA-4Ig: A genetically engineered soluble fusion protein containing the extracellular domain of CTLA-4 and the Fc portion of an immunoglobulin heavy chain (CTLA-4Ig) prevents the interaction of CD28 and CTLA-4 with their B7 ligands, the subsequent activation of T cells and thereby eliminates or reduces unfavorable immune system activation in transplant rejection or autoimmunity.

The importance of the regulatory system comprising CD28, CTLA-4 and the B7 molecules and its modulation by CTLA-4Ig has been demonstrated in a substantial number of animal models in recent years and holds promise as a novel approach for therapeutic immunomodulation in humans.