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Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115

Address correspondence to David A. Hafler, Laboratory of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115. Phone: (617) 525-5330; Fax: (617) 525-5333; email: dhafler{at}rics.bwh.harvard.edu

CD4⁺CD25⁺ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4⁺ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4⁺CD25⁺ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4⁺CD25^hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4⁺CD25^hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4⁺CD25^hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4⁺CD25^hi regulatory T cell function in patients with MS.

Key Words: tolerance • autoreactive T cells • autoimmune disease • L-selectin

Abbreviations used in this paper: CNS, central nervous system; MBP, myelin basic protein; MS, multiple sclerosis; RR, relapsing/remitting.

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• Rinaldi, L., Gallo, P., Calabrese, M., Ranzato, F., Luise, D., Colavito, D., Motta, M., Guglielmo, A., Del Giudice, E., Romualdi, C., Ragazzi, E., D'Arrigo, A., Dalle Carbonare, M., Leontino, B., Leon, A. (2006). Longitudinal analysis of immune cell phenotypes in early stage multiple sclerosis: distinctive patterns characterize MRI-active patients.. Brain 129: 1993-2007 [Abstract] [Full Text]  
• Cassan, C., Piaggio, E., Zappulla, J. P., Mars, L. T., Couturier, N., Bucciarelli, F., Desbois, S., Bauer, J., Gonzalez-Dunia, D., Liblau, R. S. (2006). Pertussis Toxin Reduces the Number of Splenic Foxp3+ Regulatory T Cells. J. Immunol. 177: 1552-1560 [Abstract] [Full Text]  
• Gold, R., Linington, C., Lassmann, H. (2006). Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Brain 129: 1953-1971 [Abstract] [Full Text]  
• Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M., Selby, W., Alexander, S. I., Nanan, R., Kelleher, A., de St. Groth, B. F. (2006). Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. JEM 203: 1693-1700 [Abstract] [Full Text]  
• Liu, W., Putnam, A. L., Xu-yu, Z., Szot, G. L., Lee, M. R., Zhu, S., Gottlieb, P. A., Kapranov, P., Gingeras, T. R., de St. Groth, B. F., Clayberger, C., Soper, D. M., Ziegler, S. F., Bluestone, J. A. (2006). CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. JEM 203: 1701-1711 [Abstract] [Full Text]  
• Alard, P., Manirarora, J. N., Parnell, S. A., Hudkins, J. L., Clark, S. L., Kosiewicz, M. M. (2006). Deficiency in NOD Antigen-Presenting Cell Function May Be Responsible for Suboptimal CD4+CD25+ T-Cell-Mediated Regulation and Type 1 Diabetes Development in NOD Mice.. Diabetes 55: 2098-2105 [Abstract] [Full Text]  
• Xu, D., Fu, J., Jin, L., Zhang, H., Zhou, C., Zou, Z., Zhao, J.-M., Zhang, B., Shi, M., Ding, X., Tang, Z., Fu, Y.-X., Wang, F.-S. (2006). Circulating and Liver Resident CD4+CD25+ Regulatory T Cells Actively Influence the Antiviral Immune Response and Disease Progression in Patients with Hepatitis B. J. Immunol. 177: 739-747 [Abstract] [Full Text]  
• Lunemann, J. D., Edwards, N., Muraro, P. A., Hayashi, S., Cohen, J. I., Munz, C., Martin, R. (2006). Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain 129: 1493-1506 [Abstract] [Full Text]  

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