Costimulatory pathways as a basic mechanisms of activating a tolerance signal in T cells.

Immune tolerance is an active response leading to the T cell unresponsiveness in the presence of the graft, which may develop through a couple of mechanisms including costimulation blockade. The CD28/B7 and CD40L/CD40 costimulatory pathways have been described as the critical for T cell activation. When activated T cell upregulate CTLA4, which importance as a negative regulatory costimulatory molecule is highlighted by the recent evidence suggesting that CTLA4 may function as a master switch for peripheral T cell tolerance. The effects of CTLA4 engagement are directed at the inhibition of CD28 signaling. Modulation of proximal TCR signals and down-stream effector pathways of T cell activation result in altered T cell differentiation and downregulation of immune responses. CTLA4 may regulate signal transduction in a rare subset of CD4+CD25 + T cells which leads to differentiation into regulatory cells. CD40L/CD40 interaction provides a bi-directional signal for T and B cell activation. A possible mechanisms of tolerance induction by CD40L/CD40 blockade involve reduction in expression of B7 molecules, effects on bcl-xL gene and APC function modification. The role of the new discovered pathways: ICOS/B7RP-I and PD-I/PD-LI in regulation of T cell response in transplantation is becoming apparent.