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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901329v1 183/6/3742    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zheng, J. Articles by Tu, W. PubMed PubMed Citation Articles by Zheng, J. Articles by Tu, W.

Efficient Induction and Expansion of Human Alloantigen-Specific CD8 Regulatory T Cells from Naive Precursors by CD40-Activated B Cells¹

Jian Zheng^*, Yinping Liu^*, Gang Qin^*, Ping-Lung Chan^*, Huawei Mao^*, Kwok-Tai Lam^*, David B. Lewis, Yu-Lung Lau^2,* and Wenwei Tu^2,*

^* Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, People’s Republic of China; and Department of Pediatrics and Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305

Although recent studies have focused on CD4⁺ regulatory T cells (Treg), CD8⁺ Treg have also been reported to play important roles in the induction and maintenance of immune tolerance. Adoptive transfer of CD8⁺ Treg in rodents or induction of CD8⁺ Treg in humans can prevent or treat allograft rejection and autoimmune diseases. However, no approaches have been reported for the generation of human Ag-specific CD8⁺ Treg at a practical scale for clinical use. Here, we found that two novel CD8⁺ T cell subsets with different levels of CD8 surface expression, CD8^high and CD8^low, could be induced from naive CD8⁺ precursors in vitro by allogeneic CD40-activated B cells, whereas only CD8^high T cells were alloantigen-specific Treg with relatively poor alloantigen-specific cytotoxicity. Importantly, alloantigen-specific CD8^high Treg could be induced and expanded from naive CD8⁺CD25^– T cells at a large scale after 3 wk of culture without exogenous cytokines. These induced alloantigen-specific Treg were CD45RO⁺ and CCR7^– memory cells, and they expressed Foxp3, CD25, CD27, CD28, and CD62L. The induction and expansion of CD8^high Treg by CD40-activated B cells were dependent on endogenously expressed IFN-, IL-2, IL-4, and CTLA-4. This approach may facilitate the clinical application of CD8⁺ Treg-based immunotherapy in transplantation and autoimmune diseases.

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 Seed Funding for Basic Research, University Research Committee, University of Hong Kong, Hong Kong SAR, People’s Republic of China (to W.T.); Edward Sai-Kim Hotung Pediatric Education and Research Fund (to Y.L.L. and W.T.); and the University of Hong Kong Postgraduate Studentships (to J.Z., G.Q., P.L.C., and H.M.).

² Address correspondence and reprint requests to Dr. Wenwei Tu, Department of Pediatrics and Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Room L7-58, 7/F Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, People’s Republic of China. E-mail address: wwtu{at}hkucc.hku.hk or Dr. Yu-Lung Lau, Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital, Faculty of Medicine, University of Hong Kong, Pokfulam, Hong Kong, People’s Republic of China. E-mail address: lauylung{at}hkucc.hku.hk

³ Abbreviations used in this paper: Treg, regulatory T cell; CMA, concanamycin A; DiO, 3,3'-dioctadecyloxacarbocyanine perchlorate; GITR, glucocorticoid-induced TNF receptor; pDC, plasmacytoid dendritic cell.

⁴ The online version of this article contains supplemental material.

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The JI 2009 183: 3557-3558. [Full Text]