Persistent TNF-α exposure impairs store operated calcium influx in CD4+ T lymphocytes

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Abstract
Persistent tumour necrosis factor alpha (TNF-α) exposure uncouples proximal T-cell receptor (TCR)-signalling events. Here, we demonstrate that chronic TNF-α exposure also attenuates signalling distal to the TCR, by specifically inhibiting Ca 2+ influx evoked by thapsigargin in CD4+ T-cells. Mitogen-induced Ca 2+ responses were impaired in a dose dependent manner, and TCR-induced Ca 2+ responses were also significantly reduced. The impairment of Ca 2+ influx strongly correlated with poor function as proliferative responses to both mitogen and anti-CD3/CD28 stimulation were suppressed. Our findings show that persistent TNF-α exposure of T-cells specifically inhibits store operated Ca 2+ influx. This may affect gene activation and contribute to the poor T-cell function in chronic inflammatory disease.