title: The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells.
abstract: Myeloid-derived suppressor cells (MDSCs) play an important role in the regulation of the immune response. MDSC expansion occurs in many circumstances, including cancer, inflammation, stresses, and transplant tolerance. Liver transplants in mice are spontaneously accepted, but hepatocyte transplants are acutely rejected, suggesting the immunoregulatory activities of liver nonparenchymal cells. We have reported that hepatic stellate cells (HpSCs), the stromal cells in the liver, are immensely immunosuppressive and can effectively protect islet transplants via induction of MDSCs. The present study shows that the addition of HpSCs into dendritic cell (DC) culture promoted development of MDSCs, instead of DCs, which was highly dependent on complement component 3 (C3) from HpSCs. The C3(-/-) HpSCs lost their ability to induce MDSCs and, consequently, failed to protect the cotransplanted islet allografts. HpSCs produced complement activation factor B and factor D which then enhanced C3 cleavage to activation products iC3b and C3d. Addition of exogenous iC3b, but not C3d, into the DC culture led to the differentiation of MDSCs with potent immune-inhibitory function. These findings provide novel mechanistic insights into the differentiation of myeloid cells mediated by local tissue cells, and may assist in the development of MDSC-based therapy in clinical settings.
authors.affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Hsieh
authors.forename: Hong-Shiue
authors.initials: HS
authors.lastname: Chou
authors.forename: Horng-Ren
authors.initials: HR
authors.lastname: Yang
authors.forename: Feng
authors.initials: F
authors.lastname: Lin
authors.forename: Sumantha
authors.initials: S
authors.lastname: Bhatt
authors.forename: Jie
authors.initials: J
authors.lastname: Qin
authors.forename: Lianfu
authors.initials: L
authors.lastname: Wang
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.forename: Shiguang
authors.initials: S
authors.lastname: Qian
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D003176:Complement C3 / Q000502:physiology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D005434:Flow Cytometry; D006085:Graft Survival; D055166:Hepatic Stellate Cells / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D007124:Immunoenzyme Techniques; D007165:Immunosuppression Therapy; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000166:cytology / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D003176:Complement C3; D012333:RNA, Messenger