Accuri C6 Flow Cytometer System
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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0303119

Received for publication March 25, 2003.
Revised October 6, 2003.
Accepted for publication October 21, 2003.

Article

Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication

Shu-Fen Wu *, Tan-Mei Liu {dagger}, Yu-Chun Lin {ddagger}, Huey-Kang Sytwu *{dagger}{ddagger}@, Hsueh-Fen Juan §, Shui-Tein Chen §, Kuo-Liang Shen ||, Sheng-Chuan Hsi **, and Shie-Liang Hsieh {dagger}{dagger}

*Graduate Institute of Life Sciences, Departments of {dagger}Microbiology and Immunology, {ddagger}Medicine, and ||Surgery, National Defense Medical Center, Taipei, Taiwan; {dagger}{dagger}Department of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan; §Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan; Department of Chemical Engineering, National Taipei University of Technology, Taiwan; and **Division of General Surgery, Armed Force Taoyuan General Hospital, Taiwan

@ To whom correspondence should be addressed. E-mail: sytwu{at}ndmctsgh.edu.tw.


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Abstract

To investigate the regulatory effects of decoy receptor 3 (DcR3) on the differentiation and function of dendritic cells (DCs), bone marrow-derived DCs (BM-DCs) from nonobese diabetic (NOD) mice were cultured with recombinant DcR3.Fc protein. Their differentiating phenotypes and T cell-stimulating functions were then evaluated. Expression of CD11c, CD40, CD54, and major histocompatibility complex I-Ag7 was reduced in cells cultured with additional DcR3.Fc, compared with DCs incubated with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, indicating that DcR3 interferes with the differentiation and maturation of BM-DCs. One of the most striking effects of DcR3.Fc on the differentiation of DCs was the up-regulation of CD86 and down-regulation of CD80, suggesting a modulatory potential to skew the T cell response toward the T helper cell type 2 (Th2) phenotype. Consistent with this, the proliferation of CD4+ T cells cocultured with DcR3.Fc-treated DCs was significantly reduced compared with that of T cells stimulated by normal DCs. Moreover, the secretion of interferon-{gamma} from T cells cocultured with DcR3.Fc-treated DCs was profoundly suppressed, indicating that DcR3 exerts a Th1-suppressing effect on differentiating DCs. Furthermore, adoptive transfer experiments revealed that NOD/severe combined immunodeficiency mice received DcR3.Fc-treated DCs, and subsequently, autoreactive T cells showed delayed onset of diabetes and a decrease in diabetic severity compared with mice that received normal DCs and T cells, suggesting a future therapeutic potential in autoimmune diabetes. Data from two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight analysis show an up-regulation of some proteins--such as mitogen-activated protein kinase p38 {beta}, cyclin-dependent kinase 6, and signal- induced proliferation-associated gene 1--and a down-regulation of the IL-17 precursor; tumor necrosis factor-related apoptosis-inducing ligand family member-associated nuclear factor-{kappa}B activator-binding kinase 1; and Golgi S-nitroso-N-acetylpenicillamine in cells treated with DcR3, further demonstrating its effect on DC differentiation and function.

Key Words: CD80 • CD86 • IFN-{gamma} • proteomics




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