FIGURE 7.

Model of ROS-induced suppression of T lymphocyte migration. (1) Several pathologies result in accumulation of high levels of ROS, including wounds, chronic infection, and cancer. (2) Chemokine stimulation also produces exogenous H₂O₂ through NOX2/DUOX enzymes, which are known to be expressed on T lymphocytes. (3) Signaling concentrations of exogenous H₂O₂ enters the cell through aquaporin channels and can manipulate proteins in the cytosol. (4) H₂O₂ signals through SFKs to internalize chemokine receptor CXCR3; internalization could occur through arrestin recruitment/clathrin-coated pits, caveolae, or an independent mechanism. Once internalized, CXCR3 is degraded in the endosome. (5) H₂O₂ also signals through SFKs to phosphorylate and activate SHIP-1. SHIP-1 activation inhibits the ability of CXCL11 to dephosphorylate cytoskeletal proteins ERM, and (6) inhibits actin polarization. H₂O₂ also increases total F-actin. (7) Collectively, chemokine internalization, SHIP-1 activation, and actin regulation reduce cytoskeletal reorganization and cell chemotaxis. (8) Proposed outcomes of migration deficiency in T lymphocytes.