Abstract
H2O2 is an early danger cue required for innate immune cell recruitment to wounds. To date, little is known about whether H2O2 is required for the migration of human adaptive immune cells to sites of inflammation. However, oxidative stress is known to impair T cell activity, induce actin stiffness, and inhibit cell polarization. In this study, we show that low oxidative concentrations of H2O2 also impede chemokinesis and chemotaxis of previously activated human T cells to CXCL11, but not CXCL10 or CXCL12. We show that this deficiency in migration is due to a reduction in inflammatory chemokine receptor CXCR3 surface expression and cellular activation of lipid phosphatase SHIP-1. We demonstrate that H2O2 acts through an Src kinase to activate a negative regulator of PI3K signaling, SHIP-1 via phosphorylation, providing a molecular mechanism for H2O2-induced chemotaxis deficiency. We hypothesize that although H2O2 serves as an early recruitment trigger for innate immune cells, it appears to operate as an inhibitor of T lymphocyte immune adaptive responses that are not required until later in the repair process.
Highlights
Because H2O2 appears to operate as a negative regulator of T cell migration, we investigated the effect of pretreating T lymphocytes directly with H2O2 to further examine its impact on both basal and CXCL11-induced migration
To test whether Src family kinases are playing a role in H2O2-induced inhibition of T cell migration, cells were pretreated with the SFK inhibitor PP2, which abrogated downregulation of CXCR3 surface expression triggered by H2O2 (Fig. 3A)
In this study we have shown that H2O2 pretreatment induced a selective and robust inhibition of T cell chemotactic migration toward CXCL11 but not toward CXCL12 or CXCL10
Summary
Consistent with this negative role of H2O2, scavenging of extracellular H2O2 via the addition of catalase resulted in an increase of both basal and CXCL11-stimulated T cell migration (Fig. 1C), whereas heat-inactivated catalase had no effect (data not shown). Consistent with H2O2 pretreatment, pretreatment with the superoxide dismutase mimetic Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (which, like H2O2 pretreatment, increases intracellular ROS, as shown in Supplemental Fig. 2) inhibited SEB-activated T lymphocyte basal and CXCL11-induced migration (Fig. 1E).
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