T-cell activation by ethanol: a possible mechanism for immunosuppression

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Date

2007-12

Authors

Naqvi, Hassan Raza, 1976-

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Abstract

Alcohol abuse has been commonly associated with enhanced susceptibility to pathogens. Studies on the effects of ethanol on the immune system are complicated by a lack of consensus on whether ethanol activates, inhibits or has no effect on immune cells. We present data showing that acute exposure of T cells to ethanol elicits responses that broadly parallel responses seen in normally stimulated T cells such as the formation of the immune synapse, polarization of the microtubule organizing center (MTOC) to the synapse and tyrosine phosphorylation of signaling proteins as seen when the T cell Receptor (TcR) engages antigen-MHC. However, incomplete activation of the T cell signaling program leads to unresponsive or anergic T cells. Our data suggests the hypothesis that ethanol can activate T cells in a manner that leads to anergy. We have found that ethanol triggers calcium signaling and this has provided one of the primary tools for analyzing the effects of ethanol on T cells. Ethanol induced calcium transients are dose-dependent and are comparable to those triggered by low doses of anti-TcR antibody. This is important because it allows us to compare ethanol dependent signaling to that normally triggered through stimulation of the T cell receptors. Analysis of the calcium signaling pathway indicates that ethanol-stimulated calcium transients depend on calcium entry and are likely due to opening of CRAC type calcium channels. The observed calcium transients go a long way towards explaining how ethanol may stimulate T cells and provides a mechanism for immune suppression through the observed translocation of NF-AT in ethanol pulsed cells. The translocation of NF-AT is particularly important because of reports that it plays a crucial role in triggering anergy and immunosuppression. Taken together, these data can help explain how ethanol can both activate T cells and cause immunosuppression.

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