GM-CSF expanded tolerogenic CD11c+CD8a− dendritic cells can induce autoantigen specific CD4+ CD25+ Foxp3+ T regulatory cells (128.11)

Abstract

Abstract Treatment of CBA/j mice with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), a potent growth factor for dendritic cells can prevent and suppress ongoing experimental autoimmune thyroiditis (EAT). GM-CSF treatment causes expansion of CD11c+CD8a− myeloid dendritic cells (DCs) with a consequent increase in CD4+CD25+ T regulatory cells (Tregs) in an EAT model. In this study, we investigated the significance of the expansion of CD8a− myeloid DCs by GM-CSF and its direct role in inducing CD4+CD25+Foxp3+ T regs. Co-culture of CD4+ T cells with CD8a-ve DCs from GM-CSF treated mice in the presence of mouse thyroglobulin (mTg) induced an increase in the number of CD4+CD25+Foxp3+ T cells. These Foxp3+ T cells produced high levels of IL-10. These T regs could suppress the mTg specific proliferation of effector CD4+CD25− T cells, which was reversed upon addition of anti-IL10R antibodies. In contrast, GM-CSF treated CD8a+ lymphoid DCs failed to show a significant suppression of mTg specific T cell proliferation. In vivo experiments in a SCID mouse model revealed that GM-CSF treated SCID mice could induce increased numbers of Foxp3 and IL-10 expressing CD4+ T cells that were adoptively transferred from wild type CBA/j mice. These results indicate that GM-CSF acts directly on CD8a− myeloid DCs in the absence of T cells and renders them tolerogenic in that they cause expansion of CD4+Foxp3+ Tregs, which suppress mTg specific proliferation in an IL-10 dependent manner. NIH 1RO1AI058190