Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation.
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.
Angelini
Giovanna
G
Protein Biology Unit, National Cancer Research Institute, 16132 Genoa, Italy. giovanna.angelini@istge.it
Gardella
Stefania
S
Ardy
Massimo
M
Ciriolo
Maria Rosa
MR
Filomeni
Giuseppe
G
Di Trapani
Giovanna
G
Clarke
Frank
F
Sitia
Roberto
R
Rubartelli
Anna
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D023201:CD40 Ligand / Q000494:pharmacology; D002450:Cell Communication; D002469:Cell Separation / Q000379:methods; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D010084:Oxidation-Reduction; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D013438:Sulfhydryl Compounds; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D007770:L-Lactate Dehydrogenase