Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives

Abstract

Mitogenically stimulated human peripheral blood lymphocytes and T cell clones were found to have weak membrane transport activity for the disulfide cystine but strong membrane transport activity for the thiol amino acid cysteine. Cysteine, however, is represented at the lowest concentration among all protein-forming amino acids in the blood plasma. Complementary laboratory experiments have shown that the cysteine supply is indeed limiting for important lymphocyte functions. Proliferative responses of mitogenically stimulated lymphocytes and T-cell clones and the activation of cytotoxic T cells in allogeneic mixed lymphocyte cultures are strongly influenced by small variations in the extracellular cysteine concentration even in the presence of relatively high and approximately physiologic concentrations of cystine. Cysteine can be substituted by N-acetylcysteine but not by cystine. The more detailed analysis revealed that the extracellular supply of cysteine influences strongly the intracellular level of glutathione (GSH) and also the activity of the transcription factor NF kappa B that regulates the expression of several immunologically relevant genes. In vitro experiments including double-chamber experiments with macrophages and lymphocytes revealed, moreover, that cysteine plays an important role as a regulatory mediator between these cell types. The cysteine supply is impaired directly or indirectly in several pathologic conditions that are associated with immunodeficiencies, including the acquired immune deficiency syndrome (AIDS). Cysteine or cysteine derivatives may therefore be considered for the treatment of patients with HIV-1 infection.