Volume 5 Supplement 1

23rd European Workshop for Rheumatology Research

Open Access

TNF suppresses CD4+ T-CELL responses by attenuating calcium/NFAT-dependent but not ERK-dependent signal transduction pathways

  • JM Clark1,
  • K Aleksiyadis1,
  • N Panesar1 and
  • AP Cope1
Arthritis Res Ther20035(Suppl 1):98

https://doi.org/10.1186/ar728

Received: 14 January 2003

Published: 24 February 2003

Background

Chronic exposure of CD4+ T cells to picomolar concentrations of tumour necrosis factor alpha (TNF) induces a hyporesponsive phenotype, as measured by T-cell-receptor-(TCR)-stimulated proliferation and cytokine production, which is similar to that of T cells recovered from inflamed rheumatoid synovial joints. We have reported previously that chronic exposure to TNF impairs assembly of the TCR/CD3 complex at the cell surface by down-regulating expression of the signal amplification module TCR zeta (TCR-ζ). TCR-induced tyrosine phosphorylation of ZAP-70, LAT and PLC-γ1 are attenuated in TNF-treated cells as a consequence.

Objective and results

Here we report studies of the effects of TNF on downstream signalling pathways using a murine T-cell hybridoma. We show that signalling from the TCR via the extracellular signal-regulated kinase (ERK) pathway is similar in control and TNF-treated cells, as determined by induction of GTP-bound Ras, by phosphorylation on ERK1/2 and the ERK substrate Elk-1, and by ERK-dependent expression of c-fos and CD69. By contrast, TCR-induced calcium flux is greatly attenuated in TNF-treated cells. Despite preservation of ERK signalling, induction of cytokine mRNA transcripts, whose expression depends upon calcium signals and the generation of NFAT (functional nuclear factor of activated T cells) or NFAT/AP-1 complexes, is markedly suppressed in TNF-treated T cells. Further experiments reveal that TNF alters signalling through the calcium/NFAT pathway independently of its effects on receptor-proximal events. For example, we find that whereas calcium responses induced by ionomycin or thapsigargin are similar in control and TNF-treated cells, IL-2 production is greatly reduced in TNF-treated cells as compared with controls after stimulation with phorbol ester and ionomycin. As is the case for stimulation via TCR, activation of the Ras/ERK pathway by phorbol ester is preserved in TNF-treated T cells.

Conclusion

These data are consistent with a model in which TNF alters NFAT function through effects on nuclear translocation, DNA binding or transcriptional activation. The model also predicts that TNF may promote T-cell effector responses indirectly by suppressing NFAT-dependent genes whose expression is required for immunoregulation and peripheral tolerance.

Authors’ Affiliations

(1)
The Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College

Copyright

© The Author(s) 2003

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