Mechanism of IL-10-induced T cell inactivation in allergic inflammation and normal response to allergens

Background Induction of specific unresponsiveness (tolerance/energy) in per ipheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy (S[T) with whole allergen or antigenic T cell peptides. Methods: Antigen-specific T cell responses a nd molecular mechanisms of T cell inactivation were investigated during con ventional SIT, T cell epitope peptide immunotherapy and natural exposure to bee venom in allergic and hyperimmune individuals. Results: T cell unrespo nsiveness, initiated by autocrine action of IL-10, is characterized by supp ressed proliferative and cytokine responses, The unresponsive T cells can b e reactivated by different cytokines that may mimic the microenvironmental cytokine influence, IL-10 initiates peripheral tolerance by blocking the CD 28 costimulatory signal in T cells. Coprecipitation experiments reveal that upon stimulation CD28 and IL-10 receptor are physically associated in T ce lls. Accordingly, IL-10 binding to its receptor inhibits CD28 tyrosine phos phorylation, the initial step of the CD28 signaling pathway. This leads to inhibition of phosphatidylinositol 3-kinase p85 binding to CD28. IL-10 only affects T cells that receive a stimulation with low numbers of triggered T cell receptors and that require costimulatory signals by CD28. Conclusion: These data demonstrate the pivotal role of autocrine IL-10 and the interac tion of its receptor with CD28 in the induction of T cell tolerance as an i mmunoregulatory mechanism controlling antigen-specific T cell responses. Co pyright (C) 2001 S. Karger AG. Basel.