Extracellular Redox Modulation by Regulatory T Cells

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2009 Sep 1

PMID 19718041

Citations 78

Authors

Zhonghua Yan

Sanjay K Garg

Jonathan Kipnis

Ruma Banerjee

Affiliations

Soon will be listed here.

Abstract

We demonstrate that the mechanism of redox remodeling during mouse T-cell activation involves secretion of glutathione by dendritic cells and its subsequent cleavage to cysteine. Extracellular cysteine accumulation results in a lower redox potential, which is conducive to proliferation, and changes the net redox status of exofacial protein domains. Regulatory T cells inhibit this redox metabolite signaling pathway, which represents a previously unrecognized mechanism for immunosuppression of effector T cells.

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References

Blakytny R, Erkell L, Brunner G . Inactivation of active and latent transforming growth factor beta by free thiols: potential redox regulation of biological action. Int J Biochem Cell Biol. 2006; 38(8):1363-73. DOI: 10.1016/j.biocel.2006.01.017. View

Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell. 2008; 133(5):775-87. DOI: 10.1016/j.cell.2008.05.009. View

Moriarty-Craige S, Jones D . Extracellular thiols and thiol/disulfide redox in metabolism. Annu Rev Nutr. 2004; 24:481-509. DOI: 10.1146/annurev.nutr.24.012003.132208. View

Gelderman K, Hultqvist M, Holmberg J, Olofsson P, Holmdahl R . T cell surface redox levels determine T cell reactivity and arthritis susceptibility. Proc Natl Acad Sci U S A. 2006; 103(34):12831-6. PMC: 1568933. DOI: 10.1073/pnas.0604571103. View

Suthanthiran M, Anderson M, Sharma V, Meister A . Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens. Proc Natl Acad Sci U S A. 1990; 87(9):3343-7. PMC: 53896. DOI: 10.1073/pnas.87.9.3343. View

Jonas C, Ziegler T, Gu L, Jones D . Extracellular thiol/disulfide redox state affects proliferation rate in a human colon carcinoma (Caco2) cell line. Free Radic Biol Med. 2002; 33(11):1499-506. DOI: 10.1016/s0891-5849(02)01081-x. View

Ramirez A, Ramadan B, Ritzenthaler J, Rivera H, Jones D, Roman J . Extracellular cysteine/cystine redox potential controls lung fibroblast proliferation and matrix expression through upregulation of transforming growth factor-beta. Am J Physiol Lung Cell Mol Physiol. 2007; 293(4):L972-81. DOI: 10.1152/ajplung.00010.2007. View

Nakamura K, Kitani A, Strober W . Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med. 2001; 194(5):629-44. PMC: 2195935. DOI: 10.1084/jem.194.5.629. View

Fallarino F, Grohmann U, Hwang K, Orabona C, Vacca C, Bianchi R . Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003; 4(12):1206-12. DOI: 10.1038/ni1003. View

10.

Ishii T, Sugita Y, Bannai S . Regulation of glutathione levels in mouse spleen lymphocytes by transport of cysteine. J Cell Physiol. 1987; 133(2):330-6. DOI: 10.1002/jcp.1041330217. View

11.

Schwertassek U, Balmer Y, Gutscher M, Weingarten L, Preuss M, Engelhard J . Selective redox regulation of cytokine receptor signaling by extracellular thioredoxin-1. EMBO J. 2007; 26(13):3086-97. PMC: 1914094. DOI: 10.1038/sj.emboj.7601746. View

12.

Markovic J, Borras C, Ortega A, Sastre J, Vina J, Pallardo F . Glutathione is recruited into the nucleus in early phases of cell proliferation. J Biol Chem. 2007; 282(28):20416-24. DOI: 10.1074/jbc.M609582200. View

13.

Vignali D, Collison L, Workman C . How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-32. PMC: 2665249. DOI: 10.1038/nri2343. View

14.

Sahaf B, Heydari K, Herzenberg L, Herzenberg L . The extracellular microenvironment plays a key role in regulating the redox status of cell surface proteins in HIV-infected subjects. Arch Biochem Biophys. 2005; 434(1):26-32. DOI: 10.1016/j.abb.2004.11.015. View

15.

Angelini G, Gardella S, Ardy M, Ciriolo M, Filomeni G, Di Trapani G . Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc Natl Acad Sci U S A. 2002; 99(3):1491-6. PMC: 122218. DOI: 10.1073/pnas.022630299. View

16.

Matthias L, Yam P, Jiang X, Vandegraaff N, Li P, Poumbourios P . Disulfide exchange in domain 2 of CD4 is required for entry of HIV-1. Nat Immunol. 2002; 3(8):727-32. DOI: 10.1038/ni815. View

17.

Sahaf B, Heydari K, Herzenberg L, Herzenberg L . Lymphocyte surface thiol levels. Proc Natl Acad Sci U S A. 2003; 100(7):4001-5. PMC: 153037. DOI: 10.1073/pnas.2628032100. View

18.

Tang Q, Bluestone J . The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008; 9(3):239-44. PMC: 3075612. DOI: 10.1038/ni1572. View

19.

Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N . The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene. 2007; 27(11):1618-28. DOI: 10.1038/sj.onc.1210796. View

20.

Nakamura H, Nakamura K, Yodoi J . Redox regulation of cellular activation. Annu Rev Immunol. 1997; 15:351-69. DOI: 10.1146/annurev.immunol.15.1.351. View