Rel B-modified dendritic cells possess tolerogenic phenotype and functions on lupus splenic lymphocytes in vitro.
Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by high morbidity and mortality and its treatment remains challenging. Dendritic cells (DCs) have been shown to participate in the initiation and perpetuation of lupus pathogenesis and the DCs that can induce tolerogenicity appear as potential cell-based therapy in this condition. In this study, we examined the in vitro tolerogenic properties of bone-marrow derived DCs (BMDCs) in the murine lupus setting. We used lentiviral transduction of RelB-silencing short hairpin RNA to modify the expression of RelB, a key transcription factor regulating DC maturation, in BMDCs from MRL/MpJ mice. Tolerogenic properties of RelB-modified DCs were compared with scrambled control (SC) -modified DCs. RelB expression was found to be significantly reduced in RelB-modified DCs derived from MRL/MpJ mice, wild-type of the same genetic background as MRL/lpr lupus-prone mice. These MRL/MpJ RelB-modified DCs displayed semi-mature phenotype with expression of lower levels of co-stimulatory molecules compared with SC-modified DCs. RelB-modified DCs were found to be low producers of interleukin-12p70 (IL-12p70) and could induce hyporesponsiveness of splenic T cells from MRL/MpJ and MRL/lpr mice. Furthermore, they down-regulated interferon-γ expression and induced IL-10-producing T cells in MRL/MpJ splenocytes, and attenuated interferon-γ and IL-17 expression in MRL/lpr splenic CD4(+) lymphocytes. Splenocytes primed by RelB-modified DCs demonstrated antigen-specific suppressive effects on allogeneic splenocytes. In conclusion, RelB-silencing in DCs generates DCs of tolerogenic properties with immunomodulatory function and appears as potential option of cell-targeted therapy.
Division of Rheumatology & Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong.
Haijing
H
Wu
Division of Rheumatology & Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong.
Yi
Y
Lo
Division of Rheumatology & Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong.
Albert
A
Chan
Division of Rheumatology & Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong.
Ka Sin
KS
Law
Division of Rheumatology & Clinical Immunology, Department of Medicine, The University of Hong Kong, Hong Kong.
Mo Yin
MY
Mok
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D034741:RNA, Small Interfering / Q000235:genetics; D013154:Spleen / Q000473:pathology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism*
D020381:Interleukin-17; D034741:RNA, Small Interfering; C497594:Relb protein, mouse; D016753:Interleukin-10; D051841:Transcription Factor RelB; D018664:Interleukin-12
dendritic cells; immune tolerance; immunotherapy; systemic lupus erythematosus; transcription factor