Hypertonic stress regulates T cell function via pannexin-1 hemichannels and P2X receptors

Hypertonic stress activates T cells by inducing the controlled release of ATP through pannexin‐1 hemichannels and activation of ATP‐gated ion channels P2X1, P2X4, and P2X7. Hypertonic saline (HS) resuscitation increases T cell function and inhibits posttraumatic T cell anergy, which can reduce immunosuppression and sepsis in trauma patients. We have previously shown that HS induces the release of cellular ATP and enhances T cell function. However, the mechanism by which HS induces ATP release and the subsequent regulation of T cell function by ATP remain poorly understood. In the present study, we show that inhibition of the gap junction hemichannel pannexin‐1 (Panx1) blocks ATP release in response to HS, and HS exposure triggers significant changes in the expression of all P2X‐type ATP receptors in Jurkat T cells. Blocking or silencing of Panx1 or of P2X1, P2X4, or P2X7 receptors blunts HS‐induced p38 MAPK activation and the stimulatory effects of HS on TCR/CD28‐induced IL‐2 gene transcription. Moreover, treatment with HS or agonists of P2X receptors overcomes T cell suppression induced by the anti‐inflammatory cytokine IL‐10. These findings indicate that Panx1 hemichannels facilitate ATP release in response to hypertonic stress and that P2X1, P2X4, and P2X7 receptor activation enhances T cell function. We conclude that HS and P2 receptor agonists promote T cell function and thus, could be used to improve T cell function in trauma patients.