Mechanism of IL-10-Induced T Cell Inactivation in Allergic Inflammation and Normal Response to Allergens

Abstract

Background: Induction of specific unresponsiveness (tolerance/anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in specific immunotherapy (SIT) with whole allergen or antigenic T cell peptides. Methods: Antigen-specific T cell responses and molecular mechanisms of T cell inactivation were investigated during conventional SIT, T cell epitope peptide immunotherapy and natural exposure to bee venom in allergic and hyperimmune individuals. Results: T cell unresponsiveness, initiated by autocrine action of IL-10, is characterized by suppressed proliferative and cytokine responses. The unresponsive T cells can be reactivated by different cytokines that may mimic the microenvironmental cytokine influence. IL-10 initiates peripheral tolerance by blocking the CD28 costimulatory signal in T cells. Coprecipitation experiments reveal that upon stimulation CD28 and IL-10 receptor are physically associated in T cells. Accordingly, IL-10 binding to its receptor inhibits CD28 tyrosine phosphorylation, 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 interaction of its receptor with CD28 in the induction of T cell tolerance as an immunoregulatory mechanism controlling antigen-specific T cell responses.

Heat denaturation, a simple method to improve the immunotherapeutic potential of allergens

“…This capacity of heatdenatured allergens to enhance the immunogenicity of allergens and to shift the cellular response towards Th1 would ideally fulfil the consensus requirements for successful SIT [1]. Although the frequencies of regulatory CD4-positive T cells and the levels of secreted IL-10 have been shown to increase in PBMC from desensitised patients [33][34][35][36], the fact that clinical symptoms develop within seconds of a bee sting suggests that neutralising antibodies play an important role in protection, unless there exist regulatory T cells that exert a more direct effect on mast cells and basophils. The importance of antibodies is further underlined by the fact that short immunotherapy with heat-denatured allergens, but not with native allergens, protected allergic mice against naturally induced anaphylaxis (Fig.…”

Overcoming Immunoescape Mechanisms of BCL1 Leukemia and Induction of CD8+ T-Cell–Mediated BCL1-Specific Resistance in Mice Cured by Targeted Polymer-Bound Doxorubicin

“…It is well established that PD-L1 and/or PD-L2 expression on APCs renders those APCs strongly tolerogenic because engagement of PD-L1 or PD-L2 with their receptor PD on T cells causes either anergy or apoptosis of these T cells (23,24). IL-10 has immunosuppressive activity on T cells, both indirectly via modulation of dendritic cell (25) and also in direct fashion (26,27), particularly by inhibiting proliferation as well as cytokine synthesis by CD4 + cells. In addition, IL-10 inhibits the monocytic production of IL-12, an essential mediator for the development of effector functions of CD8 + T cells (28)(29)(30)(31).…”

Clinical Implications and Facts About Allergic Rhinitis (AR) in Children

“…IL-10 and TGF-also inhibit the production of Th2 cytokines such as IL-4 and IL-5. , Blaser et al, 2004;Akdis et al, 2001) In addition, regulatory T cells exhibit a direct inhibitory effect on Th1 and Th2 T cells, through cell-cell contact, or by decreasing the antigen presenting function of DCs. Regulatory T cells producing IL-10 and/or TGF-b are induced not only in atopic patients by successful immunotherapy, but also during natural allergen exposure in healthy people.…”