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-a in the pathogenesis of chronic inflammatory disease is now firmly established. Paradoxically, TNF also has potent immunomodulatory ef fects on CD4(+) T lymphocytes, because Ag-specific proliferative and cytoki ne responses are suppressed following prolonged exposure to TNF. We explore d whether TNF attenuated T cell activation by uncoupling proximal TCR signa l transduction pathways using a mouse T cell hybridoma model. Chronic TNF e xposure induced profound, but reversible, T cell hyporesponsiveness, with T NF-treated T cells requiring TCR engagement with higher peptide concentrati ons for longer periods of time for commitment to IL-2 production. Subsequen t experiments revealed that chronic TNF exposure led to a reversible loss o f TCR xi chain expression, in part through a reduction in gene transcriptio n. Down-regulation of TCR xi expression impaired TCR/CD3 assembly and expre ssion at the cell surface and uncoupled membrane-proximal tyrosine phosphor ylation events, including phosphorylation of the TCR xi chain itself, CD3 e psilon, ZAP-70 protein tyrosine kinase, and linker for activation of T cell s (LAT). Intracellular Ca2+ mobilization was also suppressed in TNF-treated T cells. We propose that TNF may contribute to T cell hyporesponsiveness i n chronic inflammatory and infectious diseases by mechanisms that include d own-regulation of TCR xi expression. We speculate that by uncoupling proxim al TCR signals TNF could also interrupt mechanisms of peripheral tolerance that are dependent upon intact TCR signal transduction pathways.