Persistent TNF-alpha exposure impairs store operated calcium influx in CD4+ T lymphocytes.
Persistent tumour necrosis factor alpha (TNF-alpha) exposure uncouples proximal T-cell receptor (TCR)-signalling events. Here, we demonstrate that chronic TNF-alpha exposure also attenuates signalling distal to the TCR, by specifically inhibiting Ca2+ influx evoked by thapsigargin in CD4+ T-cells. Mitogen-induced Ca2+ responses were impaired in a dose dependent manner, and TCR-induced Ca2+ responses were also significantly reduced. The impairment of Ca2+ 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-alpha exposure of T-cells specifically inhibits store operated Ca2+ influx. This may affect gene activation and contribute to the poor T-cell function in chronic inflammatory disease.
Church
Leigh D
LD
Division of Immunity and Infection, Department of Rheumatology, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK. l.d.church@bham.ac.uk
Goodall
John E
JE
Rider
David A
DA
Bacon
Paul A
PA
Young
Stephen P
SP
D000906:Antibodies / Q000276:immunology; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000906:Antibodies; D017252:CD3 Complex; D015220:Calcium Channels; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium