REQUIREMENT FOR PROOXIDANT AND ANTIOXIDANT STATES IN T-CELL MEDIATED IMMUNE-RESPONSES - RELEVANCE FOR THE PATHOGENETIC MECHANISM OF AIDS

The discovery of decreased plasma cysteine and cystine levels and elevated plasma glutamate levels in HIV-infected patients has led to intense investigations into the role of cysteine in T cell-mediated immune responses. A large body of evidence indicates that certain aspects of the T cell response require the action of active oxygen derivatives while other aspects of the response require the action of antioxidants such as cysteine and glutathione (GSH). The prooxidant and antioxidant states may be required sequentially at different times during T cell activation. The extremely weak cystine transport activity of T cells together with oxidizing metabolites from inflammatory microenvironments appear to be important factors that support the prooxidant state. The relatively high cystine transport activity of the antigen-presenting macrophages, in contrast, provides these cells with a "cysteine pumping" function that allows the antigen binding T cells in their vicinity to shift to the antioxidant state. The difference between the membrane transport activities for cysteine of T cells and macrophages thus appears to be the key element of a mechanism that facilitates both, the prooxidant state of T cells and their regulated shift to the antioxidant state. When T cells do not receive sufficient amounts of cysteine, the intracellular GSH levels and rates of DNA synthesis activity decrease, and the cells may suffer from various manifestations of oxidative damage. Taken together, these experimental observations and conclusions suggest that the reactivity of the immune system may be influenced decisively by the operational range that is defined, on the one hand, by the strength of the prooxidant state, and on the other hand, by the capacity of the macrophages to shift the T cells to the antioxidant state. The elevated mean plasma glutamate and decreased mean cystine levels in HIV infected persons compromise this "cysteine pumping" activity and reduces thereby the operational range.