Antigen-presenting Dendritic Cells Provide the Reducing Extracellular Microenvironment Required for T Lymphocyte Activation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 Jan 17

PMID 11792859

Citations 147

Authors

Giovanna Angelini

Stefania Gardella

Massimo Ardy

Maria Rosa Ciriolo

Giuseppe Filomeni

Giovanna Di Trapani

Frank Clarke

Roberto Sitia

Anna Rubartelli

Affiliations

Soon will be listed here.

Abstract

T lymphocytes are defective in cystine uptake and thus require exogenous thiols for activation and function. Here we show that monocyte-derived human dendritic cells (DCs) release cysteine in the extracellular space. Cysteine generation is increased by lipopolysaccharide and tumor necrosis factor alpha, and by contact with T cells specifically recognizing soluble or alloantigens. These stimuli also induce thioredoxin (TRX) accumulation in DCs. However, only the contact with antigen-specific T cells triggers TRX secretion by the antigen-presenting cells. Fewer extracellular thiols are recovered after DC-T cell interactions when cystine uptake or TRX activity are inhibited. In addition, glutamate (Glu) and anti-TRX-inactivating antibodies inhibit antigen-dependent T lymphocyte proliferation. These findings indicate that, during antigen presentation, DCs uptake cystine and release cysteine and TRX, thus providing a reducing microenvironment that facilitates immune response.

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References

Mezghrani A, Courageot J, Mani J, Pugniere M, Bastiani P, Miquelis R . Protein-disulfide isomerase (PDI) in FRTL5 cells. pH-dependent thyroglobulin/PDI interactions determine a novel PDI function in the post-endoplasmic reticulum of thyrocytes. J Biol Chem. 2000; 275(3):1920-9. DOI: 10.1074/jbc.275.3.1920. View

Meister A . Glutathione-ascorbic acid antioxidant system in animals. J Biol Chem. 1994; 269(13):9397-400. View

Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu Y . Immunobiology of dendritic cells. Annu Rev Immunol. 2000; 18:767-811. DOI: 10.1146/annurev.immunol.18.1.767. View

Gardella S, Andrei C, Costigliolo S, Olcese L, Zocchi M, Rubartelli A . Secretion of bioactive interleukin-1beta by dendritic cells is modulated by interaction with antigen specific T cells. Blood. 2000; 95(12):3809-15. View

Sido B, Braunstein J, Breitkreutz R, Herfarth C, Meuer S . Thiol-mediated redox regulation of intestinal lamina propria T lymphocytes. J Exp Med. 2000; 192(6):907-12. PMC: 2193281. DOI: 10.1084/jem.192.6.907. View

Gardella S, Andrei C, Poggi A, Zocchi M, Rubartelli A . Control of interleukin-18 secretion by dendritic cells: role of calcium influxes. FEBS Lett. 2000; 481(3):245-8. DOI: 10.1016/s0014-5793(00)02015-9. View

Arner E, Holmgren A . Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000; 267(20):6102-9. DOI: 10.1046/j.1432-1327.2000.01701.x. View

Lay A, Jiang X, Kisker O, Flynn E, Underwood A, Condron R . Phosphoglycerate kinase acts in tumour angiogenesis as a disulphide reductase. Nature. 2000; 408(6814):869-73. DOI: 10.1038/35048596. View

Powis G, Montfort W . Properties and biological activities of thioredoxins. Annu Rev Pharmacol Toxicol. 2001; 41:261-95. DOI: 10.1146/annurev.pharmtox.41.1.261. View

10.

Gardella S, Andrei C, Lotti L, Poggi A, Torrisi M, Zocchi M . CD8(+) T lymphocytes induce polarized exocytosis of secretory lysosomes by dendritic cells with release of interleukin-1beta and cathepsin D. Blood. 2001; 98(7):2152-9. DOI: 10.1182/blood.v98.7.2152. View

11.

Reed D, Babson J, Beatty P, Brodie A, ELLIS W, Potter D . High-performance liquid chromatography analysis of nanomole levels of glutathione, glutathione disulfide, and related thiols and disulfides. Anal Biochem. 1980; 106(1):55-62. DOI: 10.1016/0003-2697(80)90118-9. View

12.

Ishii T, Hishinuma I, Bannai S, Sugita Y . Mechanism of growth promotion of mouse lymphoma L1210 cells in vitro by feeder layer or 2-mercaptoethanol. J Cell Physiol. 1981; 107(2):283-93. DOI: 10.1002/jcp.1041070215. View

13.

Watanabe H, Bannai S . Induction of cystine transport activity in mouse peritoneal macrophages. J Exp Med. 1987; 165(3):628-40. PMC: 2188288. DOI: 10.1084/jem.165.3.628. View

14.

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

15.

Messina J, Lawrence D . Cell cycle progression of glutathione-depleted human peripheral blood mononuclear cells is inhibited at S phase. J Immunol. 1989; 143(6):1974-81. View

16.

Rubartelli A, Cozzolino F, Talio M, Sitia R . A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence. EMBO J. 1990; 9(5):1503-10. PMC: 551842. DOI: 10.1002/j.1460-2075.1990.tb08268.x. View

17.

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

18.

Gmunder H, Eck H, Benninghoff B, Roth S, Droge W . Macrophages regulate intracellular glutathione levels of lymphocytes. Evidence for an immunoregulatory role of cysteine. Cell Immunol. 1990; 129(1):32-46. DOI: 10.1016/0008-8749(90)90184-s. View

19.

Wakasugi N, Tagaya Y, Wakasugi H, Mitsui A, Maeda M, Yodoi J . Adult T-cell leukemia-derived factor/thioredoxin, produced by both human T-lymphotropic virus type I- and Epstein-Barr virus-transformed lymphocytes, acts as an autocrine growth factor and synergizes with interleukin 1 and interleukin 2. Proc Natl Acad Sci U S A. 1990; 87(21):8282-6. PMC: 54939. DOI: 10.1073/pnas.87.21.8282. View

20.

Smyth M . Glutathione modulates activation-dependent proliferation of human peripheral blood lymphocyte populations without regulating their activated function. J Immunol. 1991; 146(6):1921-7. View