IL‐10 directly acts on T cells by specifically altering the CD28 co‐stimulation pathway

IL‐10 induces T cell anergy in numerous mouse models and specific immunotherapy of allergy in humans. Here, we demonstrate that IL‐10 directly acts on T cells which are stimulated via CD28 by efficiently blocking proliferation and cytokine production. T cells tolerized by IL‐10 showed high viability and the unresponsive state was reversed by anti‐CD3 monoclonal antibody (mAb) stimulation and IL‐2, but not by anti‐CD28 mAb stimulation. Signal transduction via CD28 requires CD28 tyrosine phosphorylation and binding of phosphatidylinositol 3‐kinase. IL‐10 inhibited tyrosine phosphorylation of CD28; thus, the phosphatidylinositol 3‐kinase binding to CD28 was blocked. Consequently, IL‐10 inhibited the antigen‐induced secretion of both Th1 and Th2 cytokines, including IL‐2, IFN‐γ, IL‐4, IL‐5 and IL‐13. Furthermore, neutralization of endogenously produced IL‐10 significantly increased T cell proliferation and both Th1 and Th2 cytokine production in vitro. Using superantigen stimuli, T cell suppression by IL‐10 was merely induced at low doses when co‐stimulation by CD28 was essential. Together, these data demonstrate that IL‐10 directly acts on the CD28 signaling pathway and this represents an important T cell suppression mechanism leading to anergy.