Prolonged exposure of T cells to TNF down-regulates TCR zeta and expression of the TCR/CD3 complex at the cell surface.
A role for TNF-alpha in the pathogenesis of chronic inflammatory disease is now firmly established. Paradoxically, TNF also has potent immunomodulatory effects on CD4(+) T lymphocytes, because Ag-specific proliferative and cytokine responses are suppressed following prolonged exposure to TNF. We explored whether TNF attenuated T cell activation by uncoupling proximal TCR signal transduction pathways using a mouse T cell hybridoma model. Chronic TNF exposure induced profound, but reversible, T cell hyporesponsiveness, with TNF-treated T cells requiring TCR engagement with higher peptide concentrations for longer periods of time for commitment to IL-2 production. Subsequent experiments revealed that chronic TNF exposure led to a reversible loss of TCRzeta chain expression, in part through a reduction in gene transcription. Down-regulation of TCRzeta expression impaired TCR/CD3 assembly and expression at the cell surface and uncoupled membrane-proximal tyrosine phosphorylation events, including phosphorylation of the TCRzeta chain itself, CD3epsilon, ZAP-70 protein tyrosine kinase, and linker for activation of T cells (LAT). Intracellular Ca(2+) mobilization was also suppressed in TNF-treated T cells. We propose that TNF may contribute to T cell hyporesponsiveness in chronic inflammatory and infectious diseases by mechanisms that include down-regulation of TCRzeta expression. We speculate that by uncoupling proximal TCR signals TNF could also interrupt mechanisms of peripheral tolerance that are dependent upon intact TCR signal transduction pathways.
Isomäki
P
P
The Kennedy Institute of Rheumatology Division, Imperial College School of Medicine, London, United Kingdom.
Panesar
M
M
Annenkov
A
A
Clark
J M
JM
Foxwell
B M
BM
Chernajovsky
Y
Y
Cope
A P
AP
D000111:Acetylcysteine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020013:Calcium Signaling / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017637:Clonal Deletion; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006825:Hybridomas; D007108:Immune Tolerance / Q000187:drug effects; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051746:ZAP-70 Protein-Tyrosine Kinase
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D007376:Interleukin-2; C110810:LAT protein, human; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; C054979:antigen T cell receptor, zeta chain; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D000111:Acetylcysteine