Klinische Wochenschrift

, Volume 69, Issue 21–23, pp 1118–1122

Requirement for prooxidant and antioxidant states in T cell mediated immune responses. — Relevance for the pathogenetic mechanism of AIDS?

  • W. Dröge
  • H. -P. Eck
  • H. Gmünder
  • S. Mihm
Overviews

Summary

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.

Key words

Cysteine T cells HIV infection Prooxidant and antioxidant states T cell activation 

Abbreviations

AIDS

acquired immunodeficiency syndrome

BLT-esterase

Nα-benzyloxycarbonyl Ne-t-butyloxycarbonyl-L-lysine-thiobenzyl-ester-esterase

GSH

glutathione

HIV

human immunodeficiency virus

IFN-γ

interferon-γ

IL-2

interleukin 2

LPS

bacterial lipopolysaccharide

2-ME

2-mercaptoethanol

NFκB

nuclear factorκB

SIV

simian immunodeficiency virus

TNFα

tumor necrosis factorα

TPA

tetradecanoyl phorbol acetate

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Dröge W, Eck H-P, Näher H, Pekar U, Daniel V (1988) Abnormal amino add concentrations in the blood of patients with acquired immune deficiency syndrome (AIDS) may contribute to the immunological defect. Biol Chem Hoppe-Seyler 369:143–148Google Scholar
  2. 2.
    Eck H-P, Gmünder H, Hartmann M, Petzoldt D, Daniel V, Dröge W (1989) Low concentrations of acid-soluble thiol (cystine) in the blood plasma of HIV-1 infected patients. Biol Chem Hoppe-Seyler 370:101–108Google Scholar
  3. 3.
    Buhl R, Holroyd K, Mastrangeli A, Cantin AM, Jaffe HA, Wells FB, Saltini C, Crystal RG (1989) Systemic glutathione deficiency in symptom-free HIV-seropositive individuals. Lancet Dec 2:1294–1298Google Scholar
  4. 4.
    Roederer M, Stahl FJT, Raju PA, Herzenberg LA, Herzenberg LA (1991) In: 3rd TNF and related Cytokines Conference. S. Karger, Basel (in press)Google Scholar
  5. 5.
    Watanabe H, Bannai S (1987) Induction of cystine transport activity in mouse peritoneal macrophages. J Exp Med 165:628–640Google Scholar
  6. 6.
    Bannai S (1986) Exchange of cystine and glutamate across plasma membrane of human fibroblasts. J Biol Chem 261:2256–2263Google Scholar
  7. 7.
    Makowske M, Christensen HN (1982) Contrasts in transport systems for anionic amino acids in hepatocytes and a hepatoma cell line HTC. J Biol Chem 257:5663–5670Google Scholar
  8. 8.
    Takada A, Bannai S (1984) Transport of cystine in isolated rat hepatocytes in primary culture. J Biol Chem 259:2441–2445Google Scholar
  9. 9.
    Hishinuma I, Ishii T, Watanabe H, Bannai S (1986) Mouse lymphoma L1210 cells acquire a new cystine transport activity upon adaption in vitro. In Vitro Cell Dev Biol 22:127–134Google Scholar
  10. 10.
    Gmünder H, Eck H-P, Benninghoff B, Roth S, Dröge W (1990) Macrophages regulate intracellular glutathione levels of lymphocytes. Evidence for an immunoregulatory role of cysteine. Cell Immunol 129:32–46Google Scholar
  11. 11.
    Eck H-P, Dröge W (1989) Influence of the extracellular glutamate concentration on the intracellular cyst(e)ine concentration in macrophages and on the capacity to release cysteine. Biol Chem Hoppe-Seyler 370:109–113Google Scholar
  12. 12.
    Dröge W, Eck H-P, Betzler M, Drings P, Ebert W (1988) Plasma glutamate concentration and lymphocyte activity. J Cancer Clin Oncol 114:124–128Google Scholar
  13. 13.
    Eck H-P, Stahl-Hennig C, Hunsmann G, Dröge W (1991) Metabolic disorder as an early consequence of SIVmac251 infection in rhesus macaques (Macaca Mulatta). Lancet (Aug. 10) 338:346–347Google Scholar
  14. 14.
    Ishii T, Sugita Y, Bannai S (1987) Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine. J Cell Physiol 133:330–336Google Scholar
  15. 15.
    Gmünder H, Eck H-P, Dröge W (1991) Low membrane transport activity for cystine in resting and mitogenically stimulated human lymphocyte preparations and human T cell clones. Eur J Biochem 201:113–117Google Scholar
  16. 16.
    Gmünder H, Roth S, Eck H-P, Gallas H, Mihm S, Dröge W (1990) Interleukin-2 mRNA expression, lymphokine production and DNA synthesis in glutathione depleted T cells. Cell Immunol 130:520–528Google Scholar
  17. 17.
    Gmünder H, Dröge W (1991) Differential effects of glutathione depletion on T cell subsets. Cell Immunol (in press)Google Scholar
  18. 18.
    Roth S, Dröge W (1987) Regulation of T cell growth factor (TCGF) production by hydrogen peroxide. Cell Immunol 108:417–424Google Scholar
  19. 19.
    Roth S, Dröge W (1991) Regulation of interleukin 2 production, interleukin 2 mRNA expression and intracellular glutathione levels in ex vivo derived T lymphocytes by lactate. Eur J Immunol 21:1933–1937Google Scholar
  20. 20.
    Mihm S, Dröge W (1990) Intracellular glutathione level controls DNA-binding activity of NFκB-like protein(s). Immunobiol 181:245Google Scholar
  21. 21.
    Mihm S, Ennen J, Pessara U, Kurth R, Dröge W (1991) Inhibition of HIV-1 replication and NF-κB activity by cysteine and cysteine derivatives. AIDS 5:497–503Google Scholar
  22. 22.
    Staal FJT, Roederer M, Herzenberg LA, Herzenberg LA (1990) Intracellular thiols regulate activation of nuclear factorκB and transcription of human immunodeficiency virus. Proc Natl Acad Sci USA 87:9943–9947Google Scholar
  23. 23.
    Schreck R, Rieber P, Baeuerle PA (1991) Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-κB transcription factor and HIV-1. EMBO J 10:2247–2258Google Scholar
  24. 24.
    Rosen GM, Freeman BA (1984) Detection of superoxide generated by endothelial cells. Proc Natl Acad Sci USA 81:7269–7273Google Scholar
  25. 25.
    Matsubara T, Ziff M (1986) Superoxide anion release by human endothelial cells: Synergism between a phorbol ester and a calcium ionophore. J Cell Physiol 127:207–210Google Scholar
  26. 26.
    Klebanoff SJ, Vadas MA, Harlan JM, Sparks LH, Gamble JR, Agosti JM, Waltersdorph AM (1986) Stimulation of neutrophils by tumor necrosis factor. J Immunol 136:4220–4225Google Scholar
  27. 27.
    Meier B, Radeke HH, Selle S, Younes M, Sies H, Resch K, Habermehl GG (1989) Human fibroblasts release reactive oxygen species in response to interleukin-1 or tumor necrosis factor-α. Biochem J 263:539–545Google Scholar
  28. 28.
    Meier B, Radeke HH, Selle S, Habermehl GG, Resch K, Sies H (1990) Biol Chem Hoppe-Seyler 371:1021–1025Google Scholar
  29. 29.
    Cross SL, Halden NF, Lenardo MJ, Leonard WJ (1989) Functionally distinct NKκB binding sites in the immunoglobulinκ and IL-2 receptorα chain genes. Science 244:466–469Google Scholar
  30. 30.
    Collart MA, Baeuerle P, Vassalli P (1990) Regulation of tumor necrosis factor a transcription in macrophages: involvement of fourκB-like motifs and of constitutive and inducible forms of NK-κB. Mol Cell Biol 10:1498–1506Google Scholar
  31. 31.
    Reddy MM, Grieco MH (1988) Elevated soluble interleukin-2 receptor levels in serum of human immunodeficiency virus infected populations. AIDS Res and Human Retroviruses 4:115–120Google Scholar
  32. 32.
    Lahdevirta J, Maury CPJ, Teppo A-M, Repo H (1988) Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85:289–291Google Scholar
  33. 33.
    Osborn L, Kunkel S, Nabel GJ (1989) Tumor necrosis factorα and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factorκB. Proc Natl Acad Sci USA 86:2336–2340Google Scholar
  34. 34.
    Rosenberg ZF, Fauci AS (1989) Immunopathogenic mechanisms of HIV infection. Clin Immunol Immunopathol 50:S149-S156Google Scholar
  35. 35.
    Roederer M, Staal FJT, Raju PA, Ela SW, Herzenberg LA (1990) Cytokine-stimulated human immunodeficiency virus replication is inhibited by N-acety-L-cysteine. Proc Natl Acad Sci USA 87:4884–4888Google Scholar
  36. 36.
    Ullmann KS, Northrop JP, Verweij CL, Crabtree GR (1990) Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: The missing link. Annu Rev Immunol 8:421–452Google Scholar
  37. 37.
    Eck H-P, Betzler M, Schlag P, Dröge W (1990) Partial recovery of lymphocyte activity in patients with colorectal carcinoma after curative surgical treatment and return of plasma glutamate concentrations to normal levels. J Cancer Res Clin Oncol 116:648–650Google Scholar

Copyright information

© Springer-Verlag 1991

Authors and Affiliations

  • W. Dröge
    • 1
  • H. -P. Eck
    • 1
  • H. Gmünder
    • 1
  • S. Mihm
    • 1
  1. 1.Abteilung ImmunchemieDeutsches KrebsforschungszentrumHeidelberg

Personalised recommendations