HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cabbage, S. E. Articles by Goverman, J. Search for Related Content PubMed PubMed Citation Articles by Cabbage, S. E. Articles by Goverman, J.

Regulatory T Cells Maintain Long-Term Tolerance to Myelin Basic Protein by Inducing a Novel, Dynamic State of T Cell Tolerance¹

Sarah E. Cabbage^*, Eric S. Huseby^2,, Blythe D. Sather, Thea Brabb, Denny Liggitt and Joan Goverman^3,

^* Molecular and Cellular Biology Program, Department of Immunology, and Department of Comparative Medicine, University of Washington, Seattle, WA 98195

The pathogenesis of multiple sclerosis involves a breakdown in T cell tolerance to myelin proteins like myelin basic protein (MBP). Most MBP-specific T cells are eliminated by central tolerance in adult mice, however, the developmentally regulated expression of MBP allows MBP-specific thymocytes in young mice to escape negative selection. It is not known how these T cells that encounter MBP for the first time in the periphery are regulated. We show that naive MBP-specific T cells transferred into T cell-deficient mice induce severe autoimmunity. Regulatory T cells prevent disease, however, suppression of the newly transferred MBP-specific T cells is abrogated by activating APCs in vivo. Without APC activation, MBP-specific T cells persist in the periphery of protected mice but do not become anergic, raising the question of how long-term tolerance can be maintained if APCs presenting endogenous MBP become activated. Our results demonstrate that regulatory T cells induce naive MBP-specific T cells responding to nonactivated APCs to differentiate into a unique, tolerized state with the ability to produce IL-10 and TGF-1 in response to activated, but not nonactivated, APCs presenting MBP. This tolerant response depends on continuous activity of regulatory T cells because, in their absence, these uniquely tolerized MBP-specific T cells can again induce autoimmunity.

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 by grants to J.G. from the National Institutes of Health (NS043417) and from the National Multiple Sclerosis Society (3328-A-4). S.E.C. was supported in part by Public Health Service National Research Service Award T32 GM07270 from the National Institute of General Medical Sciences. E.S.H. was supported by a Samuel and Althea Stroum Endowed Diabetes Fellowship.

² Current address: Department of Immunology, Howard Hughes Medical Institute, National Jewish Medical Center, Denver, CO.

³ Address correspondence and reprint requests to Dr. Joan Goverman, Department of Immunology, University of Washington, Box 357650, Seattle, WA 98195-7650. E-mail address: goverman{at}u.washington.edu

⁴ Abbreviations used in this paper: Tr1, type I regulatory T cell; DC, dendritic cell; MBP, myelin basic protein; MS, multiple sclerosis.

This article has been cited by other articles:

				S. W. McPherson, N. D. Heuss, and D. S. Gregerson Lymphopenia-Induced Proliferation Is a Potent Activator for CD4+ T Cell-Mediated Autoimmune Disease in the Retina J. Immunol., January 15, 2009; 182(2): 969 - 979. [Abstract] [Full Text] [PDF]

				H. Zhang, J. R. Podojil, X. Luo, and S. D. Miller Intrinsic and Induced Regulation of the Age-Associated Onset of Spontaneous Experimental Autoimmune Encephalomyelitis J. Immunol., October 1, 2008; 181(7): 4638 - 4647. [Abstract] [Full Text] [PDF]

				K. Kawamura, K. A. McLaughlin, R. Weissert, and T. G. Forsthuber Myelin-Reactive Type B T Cells and T Cells Specific for Low-Affinity MHC-Binding Myelin Peptides Escape Tolerance in HLA-DR Transgenic Mice J. Immunol., September 1, 2008; 181(5): 3202 - 3211. [Abstract] [Full Text] [PDF]

				N. J. Singh, M. Cox, and R. H. Schwartz TLR Ligands Differentially Modulate T Cell Responses to Acute and Chronic Antigen Presentation J. Immunol., December 15, 2007; 179(12): 7999 - 8008. [Abstract] [Full Text] [PDF]

				M. L. Molitor-Dart, J. Andrassy, J. Kwun, H. A. Kayaoglu, D. A. Roenneburg, L. D. Haynes, J. R. Torrealba, J. L. Bobadilla, H. W. Sollinger, S. J. Knechtle, et al. Developmental Exposure to Noninherited Maternal Antigens Induces CD4+ T Regulatory Cells: Relevance to Mechanism of Heart Allograft Tolerance J. Immunol., November 15, 2007; 179(10): 6749 - 6761. [Abstract] [Full Text] [PDF]