Prolonged Exposure of T Cells to TNF Down-Regulates TCRζ and Expression of the TCR/CD3 Complex at the Cell Surface

摘要: A role for TNF-α 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 attenuated cell activation by uncoupling proximal TCR signal transduction pathways using a mouse hybridoma model. Chronic induced profound, but reversible, hyporesponsiveness, with TNF-treated cells requiring engagement higher peptide concentrations longer periods time commitment IL-2 production. Subsequent experiments revealed that led reversible loss TCRζ chain expression, part through reduction gene transcription. Down-regulation expression impaired TCR/CD3 assembly at surface uncoupled membrane-proximal tyrosine phosphorylation events, including itself, CD3e, ZAP-70 protein kinase, linker (LAT). Intracellular Ca2+ mobilization was cells. propose may contribute hyporesponsiveness infectious diseases mechanisms include down-regulation expression. speculate signals could interrupt peripheral tolerance dependent upon intact pathways.