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


CONCLUSIONS
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.
Akdis
C A
CA
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland. akdism@siaf.unizh.ch
Joss
A
A
Akdis
M
M
Blaser
K
K
D000485:Allergens / Q000276:immunology; D001514:Bee Venoms / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D017635:Clonal Anergy; D016207:Cytokines / Q000096:biosynthesis; D003888:Desensitization, Immunologic; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology* / Q000628:therapy*; D007073:Immunoglobulin E / Q000096:biosynthesis; D016753:Interleukin-10 / Q000494:pharmacology*; D008407:Mast Cells / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D053701:Receptors, Interleukin-10; D013601:T-Lymphocytes / Q000276:immunology
D000485:Allergens; D001514:Bee Venoms; D018106:CD28 Antigens; D016207:Cytokines; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases