Mechanisms of immune suppression by interleukin-10 and transforming growth factor-beta: the role of T regulatory cells

Abstract

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.

Figure 1

Suppression of Th2 cell-mediated features of allergic inflammation by T_Reg cells. T_Reg cells utilize multiple suppressor factors to regulate undesired activity of effector Th2 cells. IL-10 and TGF-β suppress IgE production and induce the non-inflammatory immunoglobulin isotypes IgG4 and IgA, respectively. Furthermore, these two cytokines directly suppress allergic inflammation induced by effector cells such as mast cells, basophils and eosinophils. In addition, Th2 cells are suppressed by T_Reg cells and can therefore no longer provide cytokines such as IL-3, IL-4, IL-5, IL-9 and IL-13. These cytokines are required for the differentiation, survival and activity of mast cells, basophils, eosinophils and mucus-producing cells, as well as for the tissue homing of Th2 cells (red line indicates suppression, black line indicates stimulation).

Figure 2

Suppression of Th1 cell-mediated features of allergic inflammation by T_Reg cells. The Th1 cytokine IFN-γ in combination with TNF-α and/or FasL, induces apoptosis of smooth muscle cells, keratinocytes and bronchial epithelial cells as essential tissue injury events in atopic dermatitis and asthma. T_Reg cells suppress the stimulation of Th0/Th1 cells, leading to the abrogation of tissue injury mechanisms (red line indicates suppression, black line indicates stimulation).