Mechanisms of interleukin‐10‐mediated immune suppression

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.