IL‐2 gene expression and NF‐kappa B activation through CD28 requires reactive oxygen production by 5‐lipoxygenase.

Activation of the CD28 surface receptor provides a major costimulatory signal for T cell activation resulting in enhanced production of interleukin‐2 (IL‐2) and cell proliferation. In primary T lymphocytes we show that CD28 ligation leads to the rapid intracellular formation of reactive oxygen intermediates (ROIs) which are required for CD28‐mediated activation of the NF‐kappa B/CD28‐responsive complex and IL‐2 expression. Delineation of the CD28 signaling cascade was found to involve protein tyrosine kinase activity, followed by the activation of phospholipase A2 and 5‐lipoxygenase. Our data suggest that lipoxygenase metabolites activate ROI formation which then induce IL‐2 expression via NF‐kappa B activation. These findings should be useful for therapeutic strategies and the development of immunosuppressants targeting the CD28 costimulatory pathway.