IL-10-Producing CD4+CD25+ Regulatory T Cells Play a Critical Role in Granulocyte-Macrophage Colony-Stimulating Factor-Induced Suppression of Experimental Autoimmune Thyroiditis

Abstract

Our earlier study showed that GM-CSF has the potential not only to prevent, but also to suppress, experimental autoimmune thyroiditis (EAT). GM-CSF-induced EAT suppression in mice was accompanied by an increase in the frequency of CD4+CD25+ regulatory T cells that could suppress mouse thyroglobulin (mTg)-specific T cell responses in vitro, but the underlying mechanism of this suppression was not elucidated. In this study we show that GM-CSF can induce dendritic cells (DCs) with a semimature phenotype, an important characteristic of DCs, which are known to play a critical role in the induction and maintenance of regulatory T cells. Adoptive transfer of CD4+CD25+ T cells from GM-CSF-treated and mTg-primed donors into untreated, but mTg-primed, recipients resulted in decreased mTg-specific T cell responses. Furthermore, lymphocytes obtained from these donors and recipients after adoptive transfer produced significantly higher levels of IL-10 compared with mTg-primed, untreated, control mice. Administration of anti-IL-10R Ab into GM-CSF-treated mice abrogated GM-CSF-induced suppression of EAT, as indicated by increased mTg-specific T cell responses, thyroid lymphocyte infiltration, and follicular destruction. Interestingly, in vivo blockade of IL-10R did not affect GM-CSF-induced expansion of CD4+CD25+ T cells. However, IL-10-induced immunosuppression was due to its direct effects on mTg-specific effector T cells. Taken together, these results indicated that IL-10, produced by CD4+CD25+ T cells that were probably induced by semimature DCs, is essential for disease suppression in GM-CSF-treated mice.

Suppression of Experimental Autoimmune Myasthenia Gravis by Granulocyte-Macrophage Colony-Stimulating Factor Is Associated with an Expansion of FoxP3+ Regulatory T Cells

“…Th2 cells induce production of IgA, IgE, and IgG subclasses that do not fix complement and produce anti-inflammatory cytokines, which may down-modulate immune responses, possibly by acting as growth and differentiation factors for Tregs (34,35). Similar to previous findings (10,11,38) in the T cell-mediated disease experimental autoimmune thyroiditis (EAT), we have shown that treatment with GM-CSF results in mobilization of CD11c ϩ /CD8␣ Ϫ DCs and a skewing of the immune response to a Th2 polarization in the EAMG mouse model. Accordingly, GM-CSF-treated mice showed only slight increases in the intracellular expression of IFN-␥ and TNF-␣ by splenocytes compared with nonimmunized control (CFA) mice, had significantly reduced levels of these cytokines, and increased production of IL-4 and IL-10 compared with control tAChR-immunized mice.…”

“…Specifically, the administration of GM-CSF was recently shown to suppress a T cell-mediated autoimmune disease, experimental autoimmune thyroiditis, while administration of fms-like tyrosine kinase receptor 3-ligand (Flt3-L) had opposite effects (10). The observed suppression associated with GM-CSF treatment was dependent upon the presence of IL-10-producing CD4 ϩ CD25 ϩ Tregs induced by tolerogenic DCs (11).…”

CD4+CD25+Tregs express an increased LAG-3 and CTLA-4 in anterior chamber-associated immune deviation

“…+ Tregs is increased in ACAID mice CD4 + CD25 + T cells have been shown to play a critical role in immune tolerance and immune responses in various diseases and experimental models of disease in rodents and humans [5,7,12]. Our study aimed to examine whether CD4 + CD25 + T cells were increased in ACAID, an eyederived immune tolerance model.…”

An overview of the pathogenic mechanisms of autoimmune thyroid disorders

“…Tregs are kept at a basal state of activation by low levels of circulating auto-antigen; the homeostatic level is sufficient to prevent the development of autoimmunity, but the clonal balance between Tregs and auto-reactive T cells could be overcome by immunogenic stimuli, such as the administration of mTG and adjuvant. [21][22] As demonstrated by the group of Prabnakar, 23 In addition to cell-mediated immune mechanisms, AITD is characterized by the secretion of antibodies(Abs) to a variety of thyroid-specific antigens, most notably thyroglobulin(Tg), and thyroid peroxidase(TPO) but also to a lesser extent the TSH receptor, the sodium iodide symporter(NIS), and most recently pendrin. 13,14 Experimental evidence in mice demonstrated that, apart from Tg, TPO is also a major antigen in chronic autoimmune thyroiditis.…”