Even a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates immunological functions of lymphocytes in vitro. At low GSSG levels, T cells cannot optimally activate the immunologically important transcription factor NF kappa B, whereas high GSSG levels inhibit the DNA binding activity of NF kappa B. The effects of GSSG are antagonized by reduced thioredoxin (TRX). As the protein tyrosine kinase activities p56lck and p59fyn are activated in intact cells by hydrogen peroxide, they are likely targets for GSSG action. These redox-regulated enzymes trigger signal cascades for NF kappa B activation and transduce signals from the T cell antigen receptor, from CD4 and CD8 molecules, and from the IL-2 receptor beta-chain. The effector phase of cytotoxic T cell responses and IL-2-dependent functions are inhibited even by a partial depletion of the intracellular GSH pool. As signal transduction is facilitated by prooxidant conditions, we propose that the well-known immunological consequences of GSH depletion ultimately may be results of the accompanying GSSG deficiency. As HIV-infected patients and SIV-infected rhesus macaques have, on the average, significantly decreased plasma cyst(e)ine and intracellular GSH levels, we also hypothesize that AIDS may be the consequence of a GSSG deficiency as well.

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In order to determine whether the cysteine requirement of human T lineage cells is met primarily by extracellular cysteine or by cystine, amino-acid-transport activities were measured in resting and mitogenically stimulated human peripheral blood lymphocytes (PBL) and several human T cell clones and T cell tumors. The transport activity of the small neutral amino acids cysteine and alanine (ASC system) and the transport of the cationic amino acid arginine (y+ system) were found to be markedly increased after stimulation of PBL by the T cell mitogen phytohemagglutinin from Phuseolus vulgaris. The anionic transport activity for cystine and glutamate (x: system), in contrast, was extremely weak in both resting and activated human PBL and also in all human T cell lines under test. The weak system xLF activity of human T lineage cells was further confirmed by an independent line of experiments showing that an increase of the extracellular concentration of glutamate, i. e. a competitive inhibitor of cystine transport, causes a decrease in the intracellular cystine levels in cells of the promonocytic line U937, but not in T lineage cells (Molt-4). A third set of experiments showed that the rate of DNA synthesis in mitogenically stimulated human PBL is strongly influenced by variations of the extracellular cysteine level, even in cultures with relatively high and approximately physiological concentrations of cystine. Cysteine cannot be replaced in this case by the addition of corresponding amounts of cystine or methionine. This demonstrates an important functional consequence of the weak cystine transport activity of human lymphocytes. The results may be relevant for the pathogenetic mechanism of the acquired immunodeficiency syndrome, since the mean plasma cysteine concentration of human-immunodeficiency-virus-1-seropositive persons was found to be strongly decreased in comparison with that of healthy blood donors, and since the cysteine level even of healthy persons is extremely low in comparison with all other protein-forming amino acids.The quantitatively most important cysteine derivative of low molecular mass in the blood plasma is cystine, which usually occurs at a concentration of 100 -200 pM half-cystine [l, 21. The concentration of cysteine in blood plasma (10-20 pM), in contrast, is extremely low in comparison with the concentrations of all other protein-forming amino acids [l, 21. Markedly decreased plasma concentrations of cysteine have been found in human-immunodeficiency-virus-1-infected patients, including persons at early stages of the disease [ 3 ] . Some of the patients showed less than one fifth of the normal plasma level of cysteine. It was suggested that this cysteine deficiency may play a role in the pathogenetic mechanism of the progressive immunodeficiency syndrome, since earlier studies on murine lymphocyte preparations had shown that these cells have a low cystine-transport activity and depend strongly on extracellular cysteine for maintaining intracellular glutathione (GSH) levels and cell gr...

Elevated glutamate concentrations are commonly observed in tumor patients, and glutamate was recently found to competitively inhibit the membrane transport of cystine. We therefore investigated the possibility that elevated plasma glutamate levels may damage the immune system. The experiments in this report demonstrate a link between the individual plasma glutamate level and the individual immunological reactivity as measured by mitogenic responses. This correlation has been analyzed in 39 colorectal carcinoma patients, 40 oat cell carcinoma patients, 24 large cell lung carcinoma patients, and 31 apparently healthy persons (blood donors). Blood cells from all three groups of tumor patients in comparison with cells from healthy persons produced markedly reduced mitogenic responses against PWM, and all three groups of tumor patients had on average significantly elevated plasma glutamic acid concentrations. Our analysis revealed a linear regression of the logarithm of the individual plasma glutamate levels (before therapeutic treatment) on the logarithm of the corresponding mitogenic reactivity against PWM for the entire population of 134 persons tested (correlation coefficient -0.80; level of significance P less than 0.00001). A statistically significant linear correlation with a similar regression equation was also observed in the group of the healthy blood donors (n = 31; correlation coefficient -0.56; P less than 0.01), indicating that this correlation is universal and not dependent on the presence of a tumor. Mitogenically stimulated murine lymphocyte cultures revealed an inverse correlation between glutamate concentration and cell proliferation in response to the mitogens PHA and PWM.

We tested the hypothesis that the loss of immunological reactivity in HIV-1-infected persons may result partly from a virus-induced metabolic disorder. Patients who are infected with the acquired immunodeficiency syndrome (AIDS)-associated human immunodeficiency virus 1 were found to have, on average, markedly elevated and highly variable plasma glutamate concentrations. A similar elevation of the extracellular glutamate concentration was found to inhibit DNA synthesis in cultures of mitogenically stimulated lymphocytes. An even stronger inhibition was seen with the structural analogue quisqualate, and a moderate inhibition was seen with N-methyl-D-aspartate and kainate, i.e. with well established pharmacological probes for the excitatory glutamate receptors in the vertebrate central nervous system. The inhibitory effect of glutamate was compensated by adding cysteine or relatively large numbers of 'splenic adherent cells' to the culture. Elevated extracellular glutamate levels were also found to reduce the capacity of murine macrophages, human blood monocytes, and murine fibroblastoid cells (L929 cells) to release acid-soluble thiol (cysteine) into the extracellular space. The three cell types differed, however, with respect to their sensitivity against the three structural analogues of glutamate. The elevated glutamate concentration was not non-specifically toxic for cultured macrophages, since glycolytic activity and arginase activity were not inhibited. Implications of these observations for the pathogenetic mechanism of AIDS are discussed.