IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway.
IL-10 induces T cell anergy in numerous mouse models and specific immunotherapy of allergy in humans. Here, we demonstrate that IL-10 directly acts on T cells which are stimulated via CD28 by efficiently blocking proliferation and cytokine production. T cells tolerized by IL-10 showed high viability and the unresponsive state was reversed by anti-CD3 monoclonal antibody (mAb) stimulation and IL-2, but not by anti-CD28 mAb stimulation. Signal transduction via CD28 requires CD28 tyrosine phosphorylation and binding of phosphatidylinositol 3-kinase. IL-10 inhibited tyrosine phosphorylation of CD28; thus, the phosphatidylinositol 3-kinase binding to CD28 was blocked. Consequently, IL-10 inhibited the antigen-induced secretion of both Th1 and Th2 cytokines, including IL-2, IFN-gamma, IL-4, IL-5 and IL-13. Furthermore, neutralization of endogenously produced IL-10 significantly increased T cell proliferation and both Th1 and Th2 cytokine production in vitro. Using superantigen stimuli, T cell suppression by IL-10 was merely induced at low doses when co-stimulation by CD28 was essential. Together, these data demonstrate that IL-10 directly acts on the CD28 signaling pathway and this represents an important T cell suppression mechanism leading to anergy.
Joss
A
A
Swiss Institute of Allergy and Asthma Research, Davos.
Akdis
M
M
Faith
A
A
Blaser
K
K
Akdis
C A
CA
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000276:immunology; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology* / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology*; D018089:Superantigens / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D004768:Enterotoxins; D007376:Interleukin-2; D018089:Superantigens; D016753:Interleukin-10; C031818:enterotoxin B, staphylococcal; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases