Upregulation of Heme Oxygenase-1 Endues Immature Dendritic Cells With More Potent and Durable Immunoregulatory Properties and Promotes Engraftment in a Stringent Mouse Cardiac Allotransplant Model.

Yue Zhao,Jun Yang,Ying Xiang,Lu Wang,Gang Chen,Song Chen,Guangyuan Zhao,Xia Huang,Bingyang Xu,Yu Jia

doi:10.3389/fimmu.2018.01515

Abstract

Heme oxygenase-1 (HO-1) is critical for the ability of immature dendritic cells (imDCs) to suppress T-cell responses. Induction of high HO-1 expression may markedly improve the tolerogenic capacity of imDCs. Here, we generated bone marrow-derived DCs (BMDCs) from BALB/c mice with low doses of GM-CSF and IL-4. The adherent BMDCs were obtained as imDCs. Upregulation of HO-1 in imDCs (HO-1hi-imDCs) was achieved by cobalt protoporphyrin treatment. HO-1hi-imDCs proved to be more maturation-resistant than conventional imDCs, with an enhanced ability to inhibit allogeneic T-cell proliferation stimulated by anti-CD3/CD28 antibodies. When donor-derived DC adoptive transfer was performed in a stringent mouse cardiac allotransplant model, the extent of graft prolongation observed with HO-1hi imDCs was superior to that obtained with conventional imDCs. T-cell activation and proliferation in cardiac allograft recipients was more strongly suppressed in the HO-1hi imDC transfusion group than that in the untreated imDC group. Furthermore, donor HO-1hi imDCs were able to maintain a status of high HO-1 expression and survived longer in the recipient spleens than did untreated imDCs after adoptive transfer. In vitro-generated HO-1hi imDCs had an enhanced tolerogenic capacity to modulate alloimmune responses both in vitro and in vivo, and thus may offer a novel antigen-specific and cost-effective strategy to induce transplant tolerance.

Highlights

As the professional antigen-presenting cells, dendritic cells (DCs) do not always induce proinflammatory immune responses
Fewer than 10% of the cells expressed CD83 and GR-1. Both cell populations expressed relatively low levels of CD40, CD80, CD86, and major histocompatibility complex (MHC)-II molecules; the expression of these molecules was lower in the adherent population than in the non-adherent, indicating that the adherent bone marrow-derived DCs (BMDCs) were less mature than the non-adherent BMDCs
Since the maturation of non-adherent BMDCs was more stimulated by LPS, non-adherent BMDCs treated with 1 μg/ml of LPS for 24 h were collected and used as mature dendritic cells (mDCs) in this study

Summary

Introduction

As the professional antigen-presenting cells, dendritic cells (DCs) do not always induce proinflammatory immune responses. Immunoregulation of HO-1hi imDCs in Allotransplantation dendritic cells (mDCs) that express high levels of cell-surface major histocompatibility complex (MHC) class II proteins and costimulatory molecules, whereas T-cell tolerance can be induced by immature dendritic cells (imDCs) that express much lower levels of these antigen-presenting and costimulatory molecules [2, 3]. This tolerance mainly results from the deletion of T cells, the induction of regulatory T cells (Tregs) and anergic T cells, the expression of immunomodulatory molecules (e.g., PD-L1, PD-L2, hemeoxygenase-1, HLA-G, CD95L, galectin-1, and DC-SIGN), and the production of immunosuppressive factors (e.g., IL-10, TGF-β, IDO, IL-27, NO, and CTLA4) [4,5,6,7]. The apparent pro-tolerogenic properties of imDCs make them attractive candidates for use in promoting immune tolerance after clinical solid-organ transplantation

Methods

Results

Conclusion