Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells.
Specific immune suppression and induction of tolerance are essential processes in the regulation and circumvention of immune defence. The balance between allergen-specific type 1 regulatory (Tr1) cells and T helper (Th) 2 cells appears to be decisive in the development of allergy. Tr1 cells consistently represent the dominant subset specific for common environmental allergens in healthy individuals. In contrast, there is a high frequency of allergen-specific interleukin-4 (IL-4)-secreting T cells in allergic individuals. Allergen-specific immunotherapy can induce specific Tr1 cells that abolish allergen-induced proliferation of Th1 and Th2 cells, as well as their cytokine production. Tr1 cells utilize multiple suppressor mechanisms, such as IL-10 and transforming growth factor-beta (TGF-beta) as secreted cytokines and various surface molecules, such as cytotoxic T-lymphocyte antigen 4 and programmed death-1. IL-10 only inhibits T cells stimulated by low numbers of triggered T-cell receptors, which depend on CD28 costimulation. IL-10 inhibits CD28 tyrosine phosphorylation, preventing the binding of phosphatidylinositol 3-kinase p85 and consequently inhibiting the CD28 signalling pathway. In addition, IL-10 and TGF-beta secreted by Tr1 cells skew the antibody production from immunoglobulin E (IgE) towards the non-inflammatory isotypes IgG4 and IgA, respectively. Induction of antigen-specific Tr1 cells can thus re-direct an inappropriate immune response against allergens or auto-antigens using a broad range of suppressor mechanisms.
Taylor
Alison
A
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
Verhagen
Johan
J
Blaser
Kurt
K
Akdis
Mübeccel
M
Akdis
Cezmi A
CA
D000485:Allergens / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D007167:Immunotherapy; D016753:Interleukin-10 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
D000485:Allergens; D007132:Immunoglobulin Isotypes; D016212:Transforming Growth Factor beta; D016753:Interleukin-10