Modified myeloid dendritic cells act as regulatory dendritic cells to induce anergic and regulatory T cells

Author:

Sato Katsuaki1,Yamashita Naohide1,Baba Masanori1,Matsuyama Takami1

Affiliation:

1. From the Department of Immunology and Medical Zoology, Division of Human Retroviruses, Center for Chronic Viral Diseases, School of Medicine, Kagoshima University, Kagoshima City, Kagoshima, Japan; and the Department of Advanced Medical Science, The Institute of Medical Science, University of Tokyo, Japan.

Abstract

To exploit a novel strategy to regulate T cell–mediated immunity, we established human and murine modified dendritic cells (DCs) with potent immunoregulatory properties (designed as regulatory DCs), which displayed moderately high expression levels of major histocompatibility complex (MHC) molecules and extremely low levels of costimulatory molecules compared with their normal counterparts. Unlike human normal DCs, which caused the activation of allogeneic CD4+ and CD8+ T cells, human regulatory DCs not only induced their anergic state but also generated CD4+ or CD8+regulatory T (Tr) cells from their respective naive subsets in vitro. Although murine normal DCs activated human xenoreactive T cells in vitro, murine regulatory DCs induced their hyporesponsiveness. Furthermore, transplantation of the primed human T cells with murine normal DCs into severe combined immunodeficient (SCID) mice enhanced the lethality caused by xenogeneic graft-versus-host disease (XGVHD), whereas transplantation of the primed human T cells with murine regulatory DCs impaired their ability to cause XGVHD. In addition, a single injection of murine regulatory DCs following xenogeneic or allogeneic transplantation protected the recipients from the lethality caused by XGVHD as well as allogeneic acute GVHD. Thus, the modulation of T cell–mediated immunity by regulatory DCs provides a novel therapeutic approach for immunopathogenic diseases.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference23 articles.

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2. Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38mapk are involved in IL-10-mediated selective repression of TNF-α-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells.;Sato;J Immunol.,1999

3. Induction of tolerance by IL-10-treated dendritic cells.;Steinbrink;J Immunol.,1997

4. Human peripheral blood monocyte-derived interleukin-10-induced semi-mature dendritic cells induce anergic CD4+ and CD8+ T cells via presentation of the internalized soluble antigen and cross-presentation of the phagocytosed necrotic cellular fragments.;Sato;Cell Immunol.,2002

5. Induction of interleukin 10-producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.;Jonuleit;J Exp Med.,2000

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