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

This Article Full Text Full Text (PDF, 254K) 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 Turley, S. Articles by Mathis, D. Search for Related Content PubMed PubMed Citation Articles by Turley, S. Articles by Mathis, D. Social Bookmarking                            What's this?

Physiological ß Cell Death Triggers Priming of Self-reactive T Cells by Dendritic Cells in a Type-1 Diabetes Model

Shannon Turley¹, Laurent Poirot¹, Masakazu Hattori¹, Christophe Benoist¹ and Diane Mathis^1,2

¹ Section of Immunology and Immunogenetics, Joslin Diabetes Center
² Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215

Address correspondence to Diane Mathis or Christophe Benoist, Section of Immunology and Immunogenetics, Joslin Diabetes Center and Dept. of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Pl., Boston, MA 02215. Phone: (617) 264-2745; Fax: (617) 264-2744; email: cbdm{at}joslin.harvard.edu

The prelude to type-1 diabetes is leukocyte infiltration into the pancreatic islets, or insulitis. This process begins in pancreatic lymph nodes when T lymphocytes reactive to islet ß cells encounter antigen-presenting cells (APCs) displaying peptides derived from ß cell proteins. We show here that a ripple of physiological ß cell death, which occurs at 2 wk of age in all mouse strains, precipitates the arrival of such APCs, and that the relevant APC is a dendritic cell of CD11c⁺CD11b⁺CD8^- phenotype. These findings have significant implications concerning the nature of the diabetes-provoking deficits in NOD mice, the identity of the primordial diabetogenic antigens, and our understanding of the balance between immunity and tolerance in a pathological context.

Key Words: autoimmune response • pancreas • PLN • antigen transport • apoptosis

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

This article has been cited by other articles:

• Alam, M.-u., Harken, J. A., Knorn, A.-M., Elford, A. R., Wigmore, K., Ohashi, P. S., Millar, D. G. (2009). Transgenic Expression of Hsc70 in Pancreatic Islets Enhances Autoimmune Diabetes in Response to {beta} Cell Damage. J. Immunol. 183: 5728-5737 [Abstract] [Full Text]  
• Gagnerault, M.-C., Lanvin, O., Pasquier, V., Garcia, C., Damotte, D., Lucas, B., Lepault, F. (2009). Autoimmunity during Thymectomy-Induced Lymphopenia: Role of Thymus Ablation and Initial Effector T Cell Activation Timing in Nonobese Diabetic Mice. J. Immunol. 183: 4913-4920 [Abstract] [Full Text]  
• Hamilton-Williams, E. E., Martinez, X., Clark, J., Howlett, S., Hunter, K. M., Rainbow, D. B., Wen, L., Shlomchik, M. J., Katz, J. D., Beilhack, G. F., Wicker, L. S., Sherman, L. A. (2009). Expression of Diabetes-Associated Genes by Dendritic Cells and CD4 T Cells Drives the Loss of Tolerance in Nonobese Diabetic Mice. J. Immunol. 183: 1533-1541 [Abstract] [Full Text]  
• Sutherland, A. P.R., Van Belle, T., Wurster, A. L., Suto, A., Michaud, M., Zhang, D., Grusby, M. J., von Herrath, M. (2009). Interleukin-21 Is Required for the Development of Type 1 Diabetes in NOD Mice. Diabetes 58: 1144-1155 [Abstract] [Full Text]  
• Wong, F. S., Khai Siew, L., Scott, G., Thomas, I. J., Chapman, S., Viret, C., Wen, L. (2009). Activation of Insulin-Reactive CD8 T-Cells for Development of Autoimmune Diabetes. Diabetes 58: 1156-1164 [Abstract] [Full Text]  
• Parish, I. A., Waithman, J., Davey, G. M., Belz, G. T., Mintern, J. D., Kurts, C., Sutherland, R. M., Carbone, F. R., Heath, W. R. (2009). Tissue destruction caused by cytotoxic T lymphocytes induces deletional tolerance. Proc. Natl. Acad. Sci. USA 106: 3901-3906 [Abstract] [Full Text]  
• Melli, K., Friedman, R. S., Martin, A. E., Finger, E. B., Miao, G., Szot, G. L., Krummel, M. F., Tang, Q. (2009). Amplification of Autoimmune Response through Induction of Dendritic Cell Maturation in Inflamed Tissues. J. Immunol. 182: 2590-2600 [Abstract] [Full Text]  
• Akirav, E., Kushner, J. A., Herold, K. C. (2008). {beta}-Cell Mass and Type 1 Diabetes: Going, Going, Gone?. Diabetes 57: 2883-2888 [Abstract] [Full Text]  
• Li, Q., Xu, B., Michie, S. A., Rubins, K. H., Schreriber, R. D., McDevitt, H. O. (2008). Interferon-{alpha} initiates type 1 diabetes in nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 105: 12439-12444 [Abstract] [Full Text]  
• Wang, J., Cho, S., Ueno, A., Cheng, L., Xu, B.-Y., Desrosiers, M. D., Shi, Y., Yang, Y. (2008). Ligand-Dependent Induction of Noninflammatory Dendritic Cells by Anergic Invariant NKT Cells Minimizes Autoimmune Inflammation. J. Immunol. 181: 2438-2445 [Abstract] [Full Text]  
• Huang, X., Moore, D. J., Ketchum, R. J., Nunemaker, C. S., Kovatchev, B., McCall, A. L., Brayman, K. L. (2008). Resolving the Conundrum of Islet Transplantation by Linking Metabolic Dysregulation, Inflammation, and Immune Regulation. Endocr. Rev. 29: 603-630 [Abstract] [Full Text]  
• Han, J., Zhong, J., Wei, W., Wang, Y., Huang, Y., Yang, P., Purohit, S., Dong, Z., Wang, M.-H., She, J.-X., Gong, F., Stern, D. M., Wang, C.-Y. (2008). Extracellular High-Mobility Group Box 1 Acts as an Innate Immune Mediator to Enhance Autoimmune Progression and Diabetes Onset in NOD Mice. Diabetes 57: 2118-2127 [Abstract] [Full Text]  
• Calderon, B., Suri, A., Miller, M. J., Unanue, E. R. (2008). Dendritic cells in islets of Langerhans constitutively present {beta} cell-derived peptides bound to their class II MHC molecules. Proc. Natl. Acad. Sci. USA 105: 6121-6126 [Abstract] [Full Text]  
• Oak, S., Gilliam, L. K., Landin-Olsson, M., Torn, C., Kockum, I., Pennington, C. R., Rowley, M. J., Christie, M. R., Banga, J. P., Hampe, C. S. (2008). The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes. Proc. Natl. Acad. Sci. USA 105: 5471-5476 [Abstract] [Full Text]  
• Corbett, J. A. (2008). Thioredoxin-Interacting Protein Is Killing My {beta}-cells!. Diabetes 57: 797-798 [Full Text]  
• Martin, A. P., Grisotto, M. G., Canasto-Chibuque, C., Kunkel, S. L., Bromberg, J. S., Furtado, G. C., Lira, S. A. (2008). Islet Expression of M3 Uncovers a Key Role for Chemokines in the Development and Recruitment of Diabetogenic Cells in NOD Mice. Diabetes 57: 387-394 [Abstract] [Full Text]  
• Smith, K. A., Efstathiou, S., Cooke, A. (2007). Murine Gammaherpesvirus-68 Infection Alters Self-Antigen Presentation and Type 1 Diabetes Onset in NOD Mice. J. Immunol. 179: 7325-7333 [Abstract] [Full Text]  
• Saxena, V., Ondr, J. K., Magnusen, A. F., Munn, D. H., Katz, J. D. (2007). The Countervailing Actions of Myeloid and Plasmacytoid Dendritic Cells Control Autoimmune Diabetes in the Nonobese Diabetic Mouse. J. Immunol. 179: 5041-5053 [Abstract] [Full Text]  
• Kim, S., Kim, H. S., Chung, K. W., Oh, S. H., Yun, J. W., Im, S.-H., Lee, M.-K., Kim, K.-W., Lee, M.-S. (2007). Essential Role for Signal Transducer and Activator of Transcription-1 in Pancreatic {beta}-Cell Death and Autoimmune Type 1 Diabetes of Nonobese Diabetic Mice. Diabetes 56: 2561-2568 [Abstract] [Full Text]  
• Xia, C.-Q., Peng, R., Qiu, Y., Annamalai, M., Gordon, D., Clare-Salzler, M. J. (2007). Transfusion of Apoptotic {beta}-Cells Induces Immune Tolerance to {beta}-Cell Antigens and Prevents Type 1 Diabetes in NOD Mice. Diabetes 56: 2116-2123 [Abstract] [Full Text]  
• Enzler, T., Gillessen, S., Dougan, M., Allison, J. P., Neuberg, D., Oble, D. A., Mihm, M., Dranoff, G. (2007). Functional deficiencies of granulocyte-macrophage colony stimulating factor and interleukin-3 contribute to insulitis and destruction of {beta} cells. Blood 110: 954-961 [Abstract] [Full Text]  
• del Rio, M.-L., Rodriguez-Barbosa, J.-I., Kremmer, E., Forster, R. (2007). CD103- and CD103+ Bronchial Lymph Node Dendritic Cells Are Specialized in Presenting and Cross-Presenting Innocuous Antigen to CD4+ and CD8+ T Cells. J. Immunol. 178: 6861-6866 [Abstract] [Full Text]  
• Lambe, T., Leung, J. C. H., Ferry, H., Bouriez-Jones, T., Makinen, K., Crockford, T. L., Jiang, H. R., Nickerson, J. M., Peltonen, L., Forrester, J. V., Cornall, R. J. (2007). Limited Peripheral T Cell Anergy Predisposes to Retinal Autoimmunity. J. Immunol. 178: 4276-4283 [Abstract] [Full Text]  
• Burns, N., Gold, B. (2007). The Effect of 3-Methyladenine DNA Glycosylase-Mediated DNA Repair on the Induction of Toxicity and Diabetes by the {beta}-Cell Toxicant Streptozotocin. Toxicol Sci 95: 391-400 [Abstract] [Full Text]  
• de Jersey, J., Snelgrove, S. L., Palmer, S. E., Teteris, S. A., Mullbacher, A., Miller, J. F. A. P., Slattery, R. M. (2007). beta Cells cannot directly prime diabetogenic CD8 T cells in nonobese diabetic mice. Proc. Natl. Acad. Sci. USA 104: 1295-1300 [Abstract] [Full Text]  
• Tarbell, K. V., Petit, L., Zuo, X., Toy, P., Luo, X., Mqadmi, A., Yang, H., Suthanthiran, M., Mojsov, S., Steinman, R. M. (2007). Dendritic cell-expanded, islet-specific CD4+ CD25+ CD62L+ regulatory T cells restore normoglycemia in diabetic NOD mice. JEM 204: 191-201 [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]  
• Keir, M. E., Liang, S. C., Guleria, I., Latchman, Y. E., Qipo, A., Albacker, L. A., Koulmanda, M., Freeman, G. J., Sayegh, M. H., Sharpe, A. H. (2006). Tissue expression of PD-L1 mediates peripheral T cell tolerance. JEM 203: 883-895 [Abstract] [Full Text]  
• Shi, Y., Galusha, S. A., Rock, K. L. (2006). Cutting Edge: Elimination of an Endogenous Adjuvant Reduces the Activation of CD8 T Lymphocytes to Transplanted Cells and in an Autoimmune Diabetes Model. J. Immunol. 176: 3905-3908 [Abstract] [Full Text]  
• Casares, N., Pequignot, M. O., Tesniere, A., Ghiringhelli, F., Roux, S., Chaput, N., Schmitt, E., Hamai, A., Hervas-Stubbs, S., Obeid, M., Coutant, F., Metivier, D., Pichard, E., Aucouturier, P., Pierron, G., Garrido, C., Zitvogel, L., Kroemer, G. (2005). Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. JEM 202: 1691-1701 [Abstract] [Full Text]  
• Shigihara, T., Shimada, A., Oikawa, Y., Yoneyama, H., Kanazawa, Y., Okubo, Y., Matsushima, K., Yamato, E., Miyazaki, J.-i., Kasuga, A., Saruta, T., Narumi, S. (2005). CXCL10 DNA Vaccination Prevents Spontaneous Diabetes through Enhanced {beta} Cell Proliferation in NOD Mice. J. Immunol. 175: 8401-8408 [Abstract] [Full Text]  
• Turley, S. J., Lee, J.-W., Dutton-Swain, N., Mathis, D., Benoist, C. (2005). Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc. Natl. Acad. Sci. USA 102: 17729-17733 [Abstract] [Full Text]  
• Faideau, B., Larger, E., Lepault, F., Carel, J. C., Boitard, C. (2005). Role of {beta}-Cells in Type 1 Diabetes Pathogenesis. Diabetes 54: S87-S96 [Abstract] [Full Text]  
• Chen, Z., Herman, A. E., Matos, M., Mathis, D., Benoist, C. (2005). Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. JEM 202: 1387-1397 [Abstract] [Full Text]  
• Lee, L.-F., Xu, B., Michie, S. A., Beilhack, G. F., Warganich, T., Turley, S., McDevitt, H. O. (2005). The role of TNF-{alpha} in the pathogenesis of type 1 diabetes in the nonobese diabetic mouse: Analysis of dendritic cell maturation. Proc. Natl. Acad. Sci. USA 102: 15995-16000 [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]  
• Jiang, W., Anderson, M. S., Bronson, R., Mathis, D., Benoist, C. (2005). Modifier loci condition autoimmunity provoked by Aire deficiency. JEM 202: 805-815 [Abstract] [Full Text]  
• Sundquist, M., Wick, M. J. (2005). TNF-{alpha}-Dependent and -Independent Maturation of Dendritic Cells and Recruited CD11cintCD11b+ Cells during Oral Salmonella Infection. J. Immunol. 175: 3287-3298 [Abstract] [Full Text]  
• Martinez, X., Kreuwel, H. T. C., Redmond, W. L., Trenney, R., Hunter, K., Rosen, H., Sarvetnick, N., Wicker, L. S., Sherman, L. A. (2005). CD8+ T Cell Tolerance in Nonobese Diabetic Mice Is Restored by Insulin-Dependent Diabetes Resistance Alleles. J. Immunol. 175: 1677-1685 [Abstract] [Full Text]  
• Medarova, Z., Bonner-Weir, S., Lipes, M., Moore, A. (2005). Imaging {beta}-Cell Death With a Near-Infrared Probe. Diabetes 54: 1780-1788 [Abstract] [Full Text]  
• Liadis, N., Murakami, K., Eweida, M., Elford, A. R., Sheu, L., Gaisano, H. Y., Hakem, R., Ohashi, P. S., Woo, M. (2005). Caspase-3-Dependent {beta}-Cell Apoptosis in the Initiation of Autoimmune Diabetes Mellitus. Mol. Cell. Biol. 25: 3620-3629 [Abstract] [Full Text]  
• Kleindienst, P., Wiethe, C., Lutz, M. B., Brocker, T. (2005). Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells. J. Immunol. 174: 3941-3947 [Abstract] [Full Text]  
• Bach, J.-F., Bendelac, A., Brenner, M. B., Cantor, H., De Libero, G., Kronenberg, M., Lanier, L. L., Raulet, D. H., Shlomchik, M. J., von Herrath, M. G. (2004). The Role of Innate Immunity in Autoimmunity. JEM 200: 1527-1531 [Abstract] [Full Text]  
• Levisetti, M. G., Suri, A., Frederick, K., Unanue, E. R. (2004). Absence of Lymph Nodes in NOD Mice Treated With Lymphotoxin-{beta} Receptor Immunoglobulin Protects From Diabetes. Diabetes 53: 3115-3119 [Abstract] [Full Text]  
• Lieberman, S. M., Takaki, T., Han, B., Santamaria, P., Serreze, D. V., DiLorenzo, T. P. (2004). Individual Nonobese Diabetic Mice Exhibit Unique Patterns of CD8+ T Cell Reactivity to Three Islet Antigens, Including the Newly Identified Widely Expressed Dystrophia Myotonica Kinase. J. Immunol. 173: 6727-6734 [Abstract] [Full Text]  
• Vence, L., Benoist, C., Mathis, D. (2004). Fas Deficiency Prevents Type 1 Diabetes by Inducing Hyporesponsiveness in Islet {beta}-Cell-Reactive T-Cells. Diabetes 53: 2797-2803 [Abstract] [Full Text]  
• Fallarino, F., Bianchi, R., Orabona, C., Vacca, C., Belladonna, M. L., Fioretti, M. C., Serreze, D. V., Grohmann, U., Puccetti, P. (2004). CTLA-4-Ig Activates Forkhead Transcription Factors and Protects Dendritic Cells from Oxidative Stress in Nonobese Diabetic Mice. JEM 200: 1051-1062 [Abstract] [Full Text]  
• Yadav, D., Judkowski, V., Flodstrom-Tullberg, M., Sterling, L., Redmond, W. L., Sherman, L., Sarvetnick, N. (2004). B7-2 (CD86) Controls the Priming of Autoreactive CD4 T Cell Response against Pancreatic Islets. J. Immunol. 173: 3631-3639 [Abstract] [Full Text]  
• Elliott, J. I., Higgins, C. F. (2004). Major Histocompatibility Complex Class I Shedding and Programmed Cell Death Stimulated Through the Proinflammatory P2X7 Receptor: A Candidate Susceptibility Gene for NOD Diabetes. Diabetes 53: 2012-2017 [Abstract] [Full Text]  
• Havari, E., Lennon-Dumenil, A. M., Klein, L., Neely, D., Taylor, J. A., McInerney, M. F., Wucherpfennig, K. W., Lipes, M. A. (2004). Expression of the B7.1 Costimulatory Molecule on Pancreatic {beta} Cells Abrogates the Requirement for CD4 T Cells in the Development of Type 1 Diabetes. J. Immunol. 173: 787-796 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS