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 c ytokine release, whereas cytotoxic T cells eliminate cells bearing ant igens recognized as foreign. Through its T cell receptor each T cell c an recognize a specific peptide antigen, which is presented in the con text of the major histocompatibility complex (MHC) to T helper cells b y specialized antigen-presenting cells or to cytotoxic T cells by near ly all body cells. Upon contact with its specific antigen, the T cell receptor transduces an activation signal into the T cell, leading to p roliferation, cytokine production, or efficient cytotoxicity. Costimul ation: However, a second costimulatory signal is necessary to achieve complete activation. This can be provided by the accessory T cell mole cule 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 a t the surface of T cells previously activated for 2 to 3 days and capa ble of downregulating activation. Immunosuppression by CTLA-4Ig: A gen etically engineered soluble fusion protein containing the extracellula r domain of CTL-4 and the Fc portion of an immunoglobulin heavy chain (CTLA-4Ig) prevents the interaction of CD28 and CTLA-4 with their B7 l igands, the subsequent activation T cells and thereby eliminates or re duces unfavorable immune system activation in transplant rejection or autoimmunity. Conclusion: The importance of the regulatory system comp rising CD28, CTLA-4 and the B7 molecules and its modulation by CTLA-4I g has been demonstrated in a substantial number of animal models in re cent years and hods promise as a novel approach for therapeutic immuno modulation in humans .