Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens

Manikkam Suthanthiran, M. E. Anderson, V. K. Sharma, A. Meister

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308 Citations (Scopus)

Abstract

Regulation of proliferation of normal human T lymphocytes (T cells) by glutathione (GSH) was explored with T-cell activation models that do not require accessory cell signals. L-Buthionine-(S,R)-sulfoximine (BSO), which inactivates γ-glutamylcysteine synthetase and therefore inhibits GSH synthesis, inhibited proliferation elicited by monoclonal antibodies directed at cluster designation 2 (CD2) and CD3 antigens, or by sn-1,2-dioctanoylglyerol and ionomycin. L-Buthionine-(R)-sulfoximine, which does not inactivate γ-glutamylcysteine synthetase, did not affect proliferation. BSO-induced inhibition of accessory cell-independent T-cell proliferation was not reversed by recombinant human interleukin 2, despite activation-dependent expression of interleukin 2 receptor α by T cells treated with BSO. However, BSO-associated inhibition of T-cell proliferation was reversed by GSH or GSH ester. These studies, which show that GSH can directly modulate proliferation of highly purified T cells, suggest that GSH is essential for steps close to or at DNA synthesis. The availability of methods for decreasing and for increasing GSH levels suggest therapies to produce (i) immunosuppression (of value in organ transplantation), and (ii) immunopotentiation (of potential value in treatment of immunodeficiency states such as AIDS).

Original languageEnglish
Pages (from-to)3343-3347
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume87
Issue number9
DOIs
Publication statusPublished - 12 Jun 1990
Externally publishedYes

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CD3 Antigens
Glutathione
T-Lymphocytes
DNA
Glutamate-Cysteine Ligase
Cell Proliferation
Buthionine Sulfoximine
Ionomycin
Interleukin-2 Receptors
Organ Transplantation
Immunosuppression
Interleukin-2
Esters
Acquired Immunodeficiency Syndrome
Monoclonal Antibodies
Therapeutics

Keywords

  • buthionine sulfoximine
  • glutathione ester
  • immunodeficiency
  • immunopotentiation
  • T-cell activation

ASJC Scopus subject areas

  • General

Cite this

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abstract = "Regulation of proliferation of normal human T lymphocytes (T cells) by glutathione (GSH) was explored with T-cell activation models that do not require accessory cell signals. L-Buthionine-(S,R)-sulfoximine (BSO), which inactivates γ-glutamylcysteine synthetase and therefore inhibits GSH synthesis, inhibited proliferation elicited by monoclonal antibodies directed at cluster designation 2 (CD2) and CD3 antigens, or by sn-1,2-dioctanoylglyerol and ionomycin. L-Buthionine-(R)-sulfoximine, which does not inactivate γ-glutamylcysteine synthetase, did not affect proliferation. BSO-induced inhibition of accessory cell-independent T-cell proliferation was not reversed by recombinant human interleukin 2, despite activation-dependent expression of interleukin 2 receptor α by T cells treated with BSO. However, BSO-associated inhibition of T-cell proliferation was reversed by GSH or GSH ester. These studies, which show that GSH can directly modulate proliferation of highly purified T cells, suggest that GSH is essential for steps close to or at DNA synthesis. The availability of methods for decreasing and for increasing GSH levels suggest therapies to produce (i) immunosuppression (of value in organ transplantation), and (ii) immunopotentiation (of potential value in treatment of immunodeficiency states such as AIDS).",
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AU - Meister, A.

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AB - Regulation of proliferation of normal human T lymphocytes (T cells) by glutathione (GSH) was explored with T-cell activation models that do not require accessory cell signals. L-Buthionine-(S,R)-sulfoximine (BSO), which inactivates γ-glutamylcysteine synthetase and therefore inhibits GSH synthesis, inhibited proliferation elicited by monoclonal antibodies directed at cluster designation 2 (CD2) and CD3 antigens, or by sn-1,2-dioctanoylglyerol and ionomycin. L-Buthionine-(R)-sulfoximine, which does not inactivate γ-glutamylcysteine synthetase, did not affect proliferation. BSO-induced inhibition of accessory cell-independent T-cell proliferation was not reversed by recombinant human interleukin 2, despite activation-dependent expression of interleukin 2 receptor α by T cells treated with BSO. However, BSO-associated inhibition of T-cell proliferation was reversed by GSH or GSH ester. These studies, which show that GSH can directly modulate proliferation of highly purified T cells, suggest that GSH is essential for steps close to or at DNA synthesis. The availability of methods for decreasing and for increasing GSH levels suggest therapies to produce (i) immunosuppression (of value in organ transplantation), and (ii) immunopotentiation (of potential value in treatment of immunodeficiency states such as AIDS).

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