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Apoptotic Cells Induce Immunosuppression through Dendritic Cells: Critical Roles of IFN- and Nitric Oxide¹

Guangwen Ren^2,*, Juanjuan Su^2,, Xin Zhao^*, Liying Zhang^*, Jimin Zhang^*, Arthur I. Roberts^*, Huatang Zhang, Gobardhan Das^3,* and Yufang Shi^4,*,

^* Department of Molecular Genetics, Microbiology and Immunology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854; and School of Life Science, University of Science and Technology of China and Overseas Immunobiology Team, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, Yunnan, People’s Republic of China

Apoptotic cells induce immunosuppression through unknown mechanisms. To identify the underlying molecular mediators, we examined how apoptotic cells induce immunoregulation by dendritic cells (DC). We found that administration of DC exposed to apoptotic cells (DC_ap) strongly inhibited the expansion of lymphocytes in draining lymph nodes in vivo and the subsequent Ag-specific activation of these lymphocytes ex vivo. Unexpectedly, DC_ap supported T cell activation to a similar extent as normal DC in vitro, leading to proliferation and IL-2 production, except that DC_ap did not support T cell production of IFN-. Surprisingly, when DC_ap were cocultured with normal DC, they completely lost their ability to support T cell activation, an effect reversed by anti-IFN- or inhibitors of inducible NO synthase (iNOS). As expected, exposure to apoptotic cells rendered DC_ap capable of producing much more NO in response to exogenous IFN- than normal DC. Furthermore, DC_ap from iNOS^–/– or IFN-R1^–/– mice were not inhibitory in vitro or in vivo. Therefore, the IFN--induced production of NO by apoptotic cell-sensitized DC plays a key role in apoptotic cell-mediated immunosuppression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by New Jersey Commission on Science and Technology (NJCST-2042-014-84), United States Public Health Service Grants (AI057596 and AI50222), and the National Space Biomedical Research Institute (IIH00405), which is supported by the National Aeronautics and Space Administration through the Cooperative Agreement NCC 9-58.

² G.R. and J.S. contributed equally to this work.

³ Current address: Immunology group, International Center for Genetic Engineering and Biotechnology, Aruna asaf ali Marg, New Delhi 110067, India.

⁴ Address correspondence and reprint requests to Dr. Yufang Shi, Robert Wood Johnson Medical School, Department of Molecular Genetics, Microbiology and Immunology, 661 Hoes Lane, Piscataway, NJ 08854. E-mail address: shiyu{at}umdnj.edu

⁵ Abbreviations used in this paper: DC, dendritic cell; PS, phosphatidylserine; DC_ap, DC exposed to apoptotic cell; dLN, draining lymph node; iNOS, inducible NO synthase.

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