Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 450K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lesage, S. Articles by Goodnow, C. C. Search for Related Content PubMed PubMed Citation Articles by Lesage, S. Articles by Goodnow, C. C. Social Bookmarking                            What's this?

Failure to Censor Forbidden Clones of CD4 T Cells in Autoimmune Diabetes

Sylvie Lesage, Suzanne B. Hartley, Srinivas Akkaraju, Judith Wilson, Michelle Townsend and Christopher C. Goodnow

Australian Cancer Research Foundation Genetics Lab, Medical Genome Centre, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia

Address correspondence to Christopher C. Goodnow, Australian Cancer Research Foundation Genetics Laboratory, Medical Genome Centre, John Curtin School of Medical Research, Mills Rd., PO Box 334, The Australian National University Canberra, ACT 2601 Australia. Phone: 61-26125-3621; Fax: 61-2-6125-8512; E-mail: Chris.Goodnow{at}anu.edu.au

Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet ß cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.

Key Words: autoimmune disease • diabetes mellitus type I • clonal deletion • T lymphocytes • genetic predisposition to disease

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Guimont-Desrochers, F., Beauchamp, C., Chabot-Roy, G., Dugas, V., Hillhouse, E. E., Dusseault, J., Langlois, G., Gautier-Ethier, P., Darwiche, J., Sarfati, M., Lesage, S. (2009). Absence of CD47 in vivo influences thymic dendritic cell subset proportions but not negative selection of thymocytes. Int Immunol 21: 167-177 [Abstract] [Full Text]  
• Levisetti, M. G., Lewis, D. M., Suri, A., Unanue, E. R. (2008). Weak Proinsulin Peptide-Major Histocompatibility Complexes Are Targeted in Autoimmune Diabetes in Mice. Diabetes 57: 1852-1860 [Abstract] [Full Text]  
• Myoung, J., Bahk, Y. Y., Kang, H. S., Dal Canto, M. C., Kim, B. S. (2008). Anticapsid Immunity Level, Not Viral Persistence Level, Correlates with the Progression of Theiler's Virus-Induced Demyelinating Disease in Viral P1-Transgenic Mice. J. Virol. 82: 5606-5617 [Abstract] [Full Text]  
• Mukhopadhaya, A., Hanafusa, T., Jarchum, I., Chen, Y.-G., Iwai, Y., Serreze, D. V., Steinman, R. M., Tarbell, K. V., DiLorenzo, T. P. (2008). Selective delivery of {beta} cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8+ T cells in NOD mice. Proc. Natl. Acad. Sci. USA 105: 6374-6379 [Abstract] [Full Text]  
• Chan, W. F. N., Razavy, H., Luo, B., Shapiro, A. M. J., Anderson, C. C. (2008). Development of Either Split Tolerance or Robust Tolerance along with Humoral Tolerance to Donor and Third-Party Alloantigens in Nonmyeloablative Mixed Chimeras. J. Immunol. 180: 5177-5186 [Abstract] [Full Text]  
• Yoshida, T., Jiang, F., Honjo, T., Okazaki, T. (2008). PD-1 deficiency reveals various tissue-specific autoimmunity by H-2b and dose-dependent requirement of H-2g7 for diabetes in NOD mice. Proc. Natl. Acad. Sci. USA 105: 3533-3538 [Abstract] [Full Text]  
• Jane-wit, D., Altuntas, C. Z., Monti, J., Johnson, J. M., Forsthuber, T. G., Tuohy, V. K. (2008). Sex-Defined T-Cell Responses to Cardiac Self Determine Differential Outcomes of Murine Dilated Cardiomyopathy. Am. J. Pathol. 172: 11-21 [Abstract] [Full Text]  
• Mellanby, R. J., Koonce, C. H., Monti, A., Phillips, J. M., Cooke, A., Bikoff, E. K. (2006). Loss of Invariant Chain Protects Nonobese Diabetic Mice against Type 1 Diabetes. J. Immunol. 177: 7588-7598 [Abstract] [Full Text]  
• Chen, Y.-G., Chen, J., Osborne, M. A., Chapman, H. D., Besra, G. S., Porcelli, S. A., Leiter, E. H., Wilson, S. B., Serreze, D. V. (2006). CD38 Is Required for the Peripheral Survival of Immunotolerogenic CD4+ Invariant NK T Cells in Nonobese Diabetic Mice.. J. Immunol. 177: 2939-2947 [Abstract] [Full Text]  
• Lambe, T., Leung, J. C. H., Bouriez-Jones, T., Silver, K., Makinen, K., Crockford, T. L., Ferry, H., Forrester, J. V., Cornall, R. J. (2006). CD4 T Cell-Dependent Autoimmunity against a Melanocyte Neoantigen Induces Spontaneous Vitiligo and Depends upon Fas-Fas Ligand Interactions.. J. Immunol. 177: 3055-3062 [Abstract] [Full Text]  
• Faideau, B., Lotton, C., Lucas, B., Tardivel, I., Elliott, J. F., Boitard, C., Carel, J.-C. (2006). Tolerance to Proinsulin-2 Is Due to Radioresistant Thymic Cells. J. Immunol. 177: 53-60 [Abstract] [Full Text]  
• Michaels, M. A., Kang, H.-K., Kaliyaperumal, A., Satyaraj, E., Shi, Y., Datta, S. K. (2005). A Defect in Deletion of Nucleosome-Specific Autoimmune T Cells in Lupus-Prone Thymus: Role of Thymic Dendritic Cells. J. Immunol. 175: 5857-5865 [Abstract] [Full Text]  
• Chen, Z., Benoist, C., Mathis, D. (2005). How defects in central tolerance impinge on a deficiency in regulatory T cells. Proc. Natl. Acad. Sci. USA 102: 14735-14740 [Abstract] [Full Text]  
• Byersdorfer, C. A., Schweitzer, G. G., Unanue, E. R. (2005). Diabetes Is Predicted by the {beta} Cell Level of Autoantigen. J. Immunol. 175: 4347-4354 [Abstract] [Full Text]  
• You, S., Belghith, M., Cobbold, S., Alyanakian, M.-A., Gouarin, C., Barriot, S., Garcia, C., Waldmann, H., Bach, J.-F., Chatenoud, L. (2005). Autoimmune Diabetes Onset Results From Qualitative Rather Than Quantitative Age-Dependent Changes in Pathogenic T-Cells. Diabetes 54: 1415-1422 [Abstract] [Full Text]  
• Chen, Y.-G., Choisy-Rossi, C.-M., Holl, T. M., Chapman, H. D., Besra, G. S., Porcelli, S. A., Shaffer, D. J., Roopenian, D., Wilson, S. B., Serreze, D. V. (2005). Activated NKT Cells Inhibit Autoimmune Diabetes through Tolerogenic Recruitment of Dendritic Cells to Pancreatic Lymph Nodes. J. Immunol. 174: 1196-1204 [Abstract] [Full Text]  
• Liston, A., Gray, D. H.D., Lesage, S., Fletcher, A. L., Wilson, J., Webster, K. E., Scott, H. S., Boyd, R. L., Peltonen, L., Goodnow, C. C. (2004). Gene Dosage-limiting Role of Aire in Thymic Expression, Clonal Deletion, and Organ-specific Autoimmunity. JEM 200: 1015-1026 [Abstract] [Full Text]  
• Choisy-Rossi, C.-M., Holl, T. M., Pierce, M. A., Chapman, H. D., Serreze, D. V. (2004). Enhanced Pathogenicity of Diabetogenic T Cells Escaping a Non-MHC Gene-Controlled Near Death Experience. J. Immunol. 173: 3791-3800 [Abstract] [Full Text]  
• Silveira, P. A., Dombrowsky, J., Johnson, E., Chapman, H. D., Nemazee, D., Serreze, D. V. (2004). B Cell Selection Defects Underlie the Development of Diabetogenic APCs in Nonobese Diabetic Mice. J. Immunol. 172: 5086-5094 [Abstract] [Full Text]  
• Turley, S., Poirot, L., Hattori, M., Benoist, C., Mathis, D. (2003). Physiological {beta} Cell Death Triggers Priming of Self-reactive T Cells by Dendritic Cells in a Type-1 Diabetes Model. JEM 198: 1527-1537 [Abstract] [Full Text]  
• Jang, M.-H., Seth, N. P., Wucherpfennig, K. W. (2003). Ex Vivo Analysis of Thymic CD4 T Cells in Nonobese Diabetic Mice with Tetramers Generated from I-Ag7/Class II-Associated Invariant Chain Peptide Precursors. J. Immunol. 171: 4175-4186 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS