International Immunology Advance Access originally published online on January 27, 2009
International Immunology 2009 21(3):269-282; doi:10.1093/intimm/dxn147
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GM-CSF-induced CD11c+CD8a—dendritic cells facilitate Foxp3+ and IL-10+ regulatory T cell expansion resulting in suppression of autoimmune thyroiditis
1 Department of Microbiology and Immunology
2 Department of Surgery, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
Correspondence to: B. S. Prabhakar; E-mail: bprabhak{at}uic.edu
GM-CSF plays an essential role in the differentiation of dendritic cells (DCs). Our studies have shown that GM-CSF treatment can induce semi-mature DCs and CD4+CD25+ regulatory T cells (Tregs) and suppress ongoing autoimmunity in mouse models. In this study, we examined the differences in the potential of GM-CSF to exert tolerogenic function on CD8a+ and CD8a– sub-populations of DCs in vivo. We show that GM-CSF modulates CD8a–, but not CD8a+ DCs in vivo, by inhibiting the surface expression of activation markers MHC II and CD80 and production of inflammatory cytokines such as IL-12 and IL-1β. Self-antigen [mouse thyroglobulin (mTg)] presentation by GM-CSF-exposed CD8a– DCs to T cells from mTg-primed mice induced a profound increase in the frequency of forkhead box P3 (FoxP3)-expressing T cells compared with antigen presentation by GM-CSF-exposed CD8a+ DCs and control CD8a+ and CD8a– DCs. This tolerogenic property of GM-CD8a– DCs was abrogated when IL-12 was added. GM-CSF-exposed CD8a– DCs could also induce secretion of significantly higher amounts of IL-10 by T cells from mTg-primed mice. Importantly, adoptive transfer of CD8a– DCs from GM-CSF-treated SCID mice, but not untreated mice, into wild-type CBA/J mice prevented the development of experimental autoimmune thyroiditis (EAT) in the recipient animals upon immunization with mTg. Collectively, our results show that GM-CSF renders CD8a– DCs tolerogenic, and these DCs induce Foxp3+ and IL-10+ Tregs.
Keywords: autoimmunity, dendritic cells, GM-CSF, regulatory T cells, thyroiditis, tolerance
Transmitting editor: C. Terhorst
Received 16 April 2008, accepted 17 December 2008.