A molecular basis for T cell suppression by IL‐10: CD28‐associated IL‐10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3‐kinase binding

Specific immune suppression and induction of anergy in T cells are essential processes in regulation and circumvention of immune defense. IL-10, a suppressor cytokine of T cell proliferative and cytokine responses, plays a key regulatory role in tolerizing exogenous antigens during specific immunotherapy and natural exposure. The present study demonstrates that IL-10 induces T cell suppression by blocking the CD28 costimulatory signal. T cell receptor counting and T cell proliferation studies by anti-CD3 and anti-CD28 stimulation in the presence or absence of IL-10 revealed that IL-10 only inhibits T cells stimulated by low numbers of triggered T cell receptors and that depend on CD28 costimulation. T cells receiving a strong signal by the T cell receptor alone and that do not require CD28 costimulation are therefore not affected by IL-10. Coprecipitation experiments demonstrated that CD28 and the IL-10 receptor are associated in activated T cells. IL-10 inhibited CD28 tyrosine phosphorylation, the initial step of the CD28 signaling pathway. In consequence, phosphatidylinositol 3-kinase p85 binding to CD28 was inhibited. Thus, IL-10-induced selective inhibition of the CD28 costimulatory pathway demonstrates a decisive mechanism in determining whether a T cell will contribute to an immune response or become anergic.