Specific immune suppression and induction of anergy are essential processes in the regulation and circumvention of immune defence. Interleukin-10 (IL-10), a suppressor cytokine of T-cell proliferative and cytokine responses, plays a key regulatory role in tolerizing exogenous antigens during specific immunotherapy (SIT) of allergy and natural exposure to antigens. Specific T-cell tolerance is directed against the T-cell epitopes of an antigen and characterized by suppressed proliferative and T helper type 1 (Th1) and type 2 (Th2) cytokine responses. IL-10 elicits tolerance in T cells by selective inhibition of the CD28 co-stimulatory pathway and thereby controls suppression and development of antigen-specific immunity. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors and which therefore depend on CD28 co-stimulation. T cells receiving a strong signal from the T-cell receptor alone, and thus not requiring CD28 co-stimulation, are not affected by IL-10. IL-10 inhibits CD28 tyrosine phosphorylation, the initial step of the CD28 signalling pathway, and consequently the phosphatidylinositol 3-kinase p85 binding to CD28. Together these results demonstrate that IL-10-induced selective inhibition of the CD28 co-stimulatory pathway acts as a decisive mechanism in determining whether a T cell will contribute to an immune response or become anergic.