GM-CSF-induced CD11c+CD8a--dendritic cells facilitate Foxp3+ and IL-10+ regulatory T cell expansion resulting in suppression of autoimmune thyroiditis

Abstract

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-1beta. 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.

Dendritic Cells Induce Regulatory T Cell Proliferation through Antigen-Dependent and -Independent Interactions

“…In support of its use, numerous mouse models of autoimmunity, including autoimmune diabetes and myasthenia gravis, can be ameliorated through administration of GM-CSF (26,28,29). Furthermore, GM-CSF could be potentially used to expand autologous Tregs for therapy in vitro.…”

“…Several reports investigating the mechanisms regulating the expansion and maintenance of Tregs have focused on the ability of the cytokine GM-CSF to expand this population of T cells (26)(27)(28)(29).…”

“…Moreover, in vivo administration of GM-CSF prevents or attenuates autoimmune disease in a variety of mouse models (26,28,29). The finding that GM-CSF treatment results in DC expansion and an accumulation of Tregs suggests a potential mechanism for its function in immune tolerance (26,28,29).…”

Caveolin-1–Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization

“…A large body of evidence shows that immature DCs can promote tolerance by converting naive T cells into the CD4 + Foxp3 + regulatory T cells (Tregs) (2,3). In addition, DCs alternatively activated with cholera toxin and LPS (4,5), or modified with TGF-b and GM-CSF (6,7), have also been shown to induce Tregs. However, these types of tolerogenic DCs are mostly generated in vitro, and there are numerous technical and regulatory obstacles to their use in human immunotherapy.…”

Effect of L-thyroxine treatment on peripheral blood dendritic cell subpopulations in patients with Hashimoto’s thyroiditis

“…The involvement of DCs in the pathogenesis of various forms of autoimmune thyroid disease seems to be increasingly well documented [17]. However, there are still very little data based on human studies available.…”