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Blood, 1 May 2007, Vol. 109, No. 9, pp. 4071-4079. Prepublished online as a Blood First Edition Paper on December 29, 2006; DOI 10.1182/blood-2006-10-050625. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2006-10-050625v1 109/9/4071    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zhang, D. Articles by Zheng, X. X. Search for Related Content PubMed PubMed Citation Articles by Zhang, D. Articles by Zheng, X. X. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 8, 2006 Accepted December 22, 2006 New differentiation pathway for double-negative regulatory T-cells that regulates the magnitude of immune responses Dong Zhang, Wei Yang, Nicolas Degauque, Yan Tian, Allison Mikita, and Xin Xiao Zheng* Harvard Medical School, Transplantation Research Center, Beth Israel Deaconess Medical Center, Boston, MA, United States Capital University of Medical Sciences, Beijing Friendship Hospital, Beijing, China * Corresponding author; email: xzheng{at}bidmc.harvard.edu. Recent studies have demonstrated that in peripheral lymphoid tissues of normal mice and humans, 1-5% of TCR+ T-cells are CD4-CD8- (double-negative, DN) T-cells, capable of down-regulating immune responses. However, the origin and developmental pathway of DN T-cells is still not clear. In this study, by monitoring CD4 expression during T-cell proliferation and differentiation, we identified a new differentiation pathway for the conversion of CD4+ T-cells to DN regulatory T-cells. We showed that the converted DN T-cells retained a stable phenotype after re-stimulation and furthermore, the disappearance of cell surface CD4 molecules on converted DN T-cells was a result of CD4 gene silencing. The converted DN T-cells were resistant to AICD and expressed a unique set of cell-surface markers and gene profiles. These cells were highly potent in suppressing alloimmune responses both in vitro and in vivo in an antigen specific manner. Perforin was highly expressed by the converted DN regulatory T-cells and played a role in DN T-cell mediated suppression. Our findings thus identify a new differentiation pathway for DN regulatory T-cells and uncover a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses. This pathway provides a novel, cell-based, therapeutic approach for preventing allograft rejection. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Grabner, K. Lotzer, S. Dopping, M. Hildner, D. Radke, M. Beer, R. Spanbroek, B. Lippert, C. A. Reardon, G. S. Getz, et al. Lymphotoxin {beta} receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice J. Exp. Med., January 16, 2009; 206(1): 233 - 248. [Abstract] [Full Text] [PDF] C. Vogtenhuber, M. J. O'Shaughnessy, D. A. A. Vignali, and B. R. Blazar Outgrowth of CD4low/negCD25+ T Cells with Suppressor Function in CD4+CD25+ T Cell Cultures upon Polyclonal Stimulation Ex Vivo J. Immunol., December 15, 2008; 181(12): 8767 - 8775. [Abstract] [Full Text] [PDF] M. S. Ford McIntyre, K. J. Young, J. Gao, B. Joe, and L. Zhang Cutting Edge: In Vivo Trogocytosis as a Mechanism of Double Negative Regulatory T Cell-Mediated Antigen-Specific Suppression J. Immunol., August 15, 2008; 181(4): 2271 - 2275. [Abstract] [Full Text] [PDF]

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