Dysregulation of plasma amino acid levels in HIV-infection and cancer and its relevance for the immune system

Abstract

T cells have a weak membrane transport actitivity for cystine but strong transport activity for cysteine. Even moderate variations of the cysteine concentration affect T cell functions in spite of the high concentration of cystine in cultures with physiological amino acid concentrations. The IL-2 dependent DNA synthesis and the activation of cytotoxic T cells are positively regulated by cysteine, while the activity of the transcription factor NFkB and the production of IL-2 are stimulated by active oxygen species and inhibited by cysteine or GSH. Macrophages, in contrast to T cells, take up more cystine than they need and release the excess after intracellular reduction as cysteine into the extracellular space. This "cysteine pumping activity" of macrophages raises intracellular GSH levels and DNA synthesis of T cells in the vicinity. The difference between the cystine transport activities of T cells and macrophages, therefore, enables T cells to switch between prooxidant and antioxidant states. The "cysteine pump" favors selectively the antigen-specific T cells that are about to be stimulated by antigen-presenting macrophages. The capacity of macrophages to take up cystine and to release cysteine is inhibited, however, by elevated extracellular glutamate concentrations. Elevated plasma glutamate levels have been found in several pathological conditions including cancer and HIV-infection. In HIV-infected patients, the hyperglutamataemia is aggravated by hypocystinaemia and hypocysteinaemia. Our studies, therefore, suggest that the cysteine supply is impaired in several pathological conditions with immunodeficiencies including AIDS. N-acetyl-cysteine (NAC) is a safe and well established drug that may be considered for the treatment of patients with HIV-infection.