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 Morgan, D. J. Articles by Sherman, L. A. Search for Related Content PubMed PubMed Citation Articles by Morgan, D. J. Articles by Sherman, L. A.

Antigen Concentration and Precursor Frequency Determine the Rate of CD8⁺ T Cell Tolerance to Peripherally Expressed Antigens¹

Department of Immunology, Scripps Research Institute, La Jolla, CA 92037

Expression of transgene-encoded proteins in the pancreatic islets can cause peripheral deletion of T cells. However, tolerance has not been observed in all transgenic models. It has been proposed that the determining factor for successful peripheral tolerance is the amount of Ag cross-presented by quiescent APCs. Using InsHA mice, which demonstrate peripheral tolerance to the influenza virus hemagglutinin (HA) expressed in the pancreatic islet ß cells, we have investigated the consequences when different amounts of HA are expressed. As compared with InsHA mice that are heterozygous for the InsHA transgene, homozygous InsHA mice demonstrated enhanced activation and proliferation of K^d-restricted HA-specific CD8⁺ T cells in the pancreatic lymph nodes. However, despite such activation, insulitis was not observed, and the T cells were gradually functionally deleted. Deletion of these activated cells occurred much more rapidly in homozygous than in heterozygous InsHA mice. These data demonstrate that there is a direct correlation between the amount of HA expressed in the periphery, and both the degree of T cell proliferation in the pancreatic lymph nodes and the rate of tolerance of HA-specific CD8⁺ T cells. This strongly supports the hypothesis that activation of T cells through cross-presentation of peripheral Ags in a noninflammatory environment is an important part of the normal mechanism of tolerance to Ags expressed in the pancreatic islets.

This article has been cited by other articles:

				E. E. Hamilton-Williams, X. Martinez, J. Clark, S. Howlett, K. M. Hunter, D. B. Rainbow, L. Wen, M. J. Shlomchik, J. D. Katz, G. F. Beilhack, et al. Expression of Diabetes-Associated Genes by Dendritic Cells and CD4 T Cells Drives the Loss of Tolerance in Nonobese Diabetic Mice J. Immunol., August 1, 2009; 183(3): 1533 - 1541. [Abstract] [Full Text] [PDF]

				J. A. Gebe, B. B. Yue, K. A. Unrath, B. A. Falk, and G. T. Nepom Restricted Autoantigen Recognition Associated with Deletional and Adaptive Regulatory Mechanisms J. Immunol., July 1, 2009; 183(1): 59 - 65. [Abstract] [Full Text] [PDF]

				L. Klotz, S. Hucke, D. Thimm, S. Classen, A. Gaarz, J. Schultze, F. Edenhofer, C. Kurts, T. Klockgether, A. Limmer, et al. Increased Antigen Cross-Presentation but Impaired Cross-Priming after Activation of Peroxisome Proliferator-Activated Receptor {gamma} Is Mediated by Up-Regulation of B7H1 J. Immunol., July 1, 2009; 183(1): 129 - 136. [Abstract] [Full Text] [PDF]

				D. Getnet, C. H. Maris, E. L. Hipkiss, J. F. Grosso, T. J. Harris, H.-R. Yen, T. C. Bruno, S. Wada, A. Adler, R. W. Georgantas, et al. Tumor Recognition and Self-Recognition Induce Distinct Transcriptional Profiles in Antigen-Specific CD4 T Cells J. Immunol., April 15, 2009; 182(8): 4675 - 4685. [Abstract] [Full Text] [PDF]

				P. Schuler, E. Contassot, M. Irla, S. Hugues, O. Preynat-Seauve, F. Beermann, A. Donda, L.E. French, and B. Huard Direct Presentation of a Melanocyte-Associated Antigen in Peripheral Lymph Nodes Induces Cytotoxic CD8+ T Cells Cancer Res., October 15, 2008; 68(20): 8410 - 8418. [Abstract] [Full Text] [PDF]

				F. Miyagawa, Y. Tagaya, B. S. Kim, H. J. Patel, K. Ishida, T. Ohteki, T. A. Waldmann, and S. I. Katz IL-15 Serves as a Costimulator in Determining the Activity of Autoreactive CD8 T Cells in an Experimental Mouse Model of Graft-versus-Host-Like Disease J. Immunol., July 15, 2008; 181(2): 1109 - 1119. [Abstract] [Full Text] [PDF]

				J. McGill, N. Van Rooijen, and K. L. Legge Protective influenza-specific CD8 T cell responses require interactions with dendritic cells in the lungs J. Exp. Med., July 7, 2008; 205(7): 1635 - 1646. [Abstract] [Full Text] [PDF]

				W. L. Redmond, C.-H. Wei, H. T. C. Kreuwel, and L. A. Sherman The Apoptotic Pathway Contributing to the Deletion of Naive CD8 T Cells during the Induction of Peripheral Tolerance to a Cross-Presented Self-Antigen J. Immunol., April 15, 2008; 180(8): 5275 - 5282. [Abstract] [Full Text] [PDF]

				B. J. E. Raveney and D. J. Morgan Dynamic Control of Self-Specific CD8+ T Cell Responses via a Combination of Signals Mediated by Dendritic Cells J. Immunol., September 1, 2007; 179(5): 2870 - 2879. [Abstract] [Full Text] [PDF]

				M. L. Ford, B. H. Koehn, M. E. Wagener, W. Jiang, S. Gangappa, T. C. Pearson, and C. P. Larsen Antigen-specific precursor frequency impacts T cell proliferation, differentiation, and requirement for costimulation J. Exp. Med., February 19, 2007; 204(2): 299 - 309. [Abstract] [Full Text] [PDF]

				M. Yoshino, H. Yamazaki, L. D. Shultz, and S.-I. Hayashi Constant rate of steady-state self-antigen trafficking from skin to regional lymph nodes Int. Immunol., November 1, 2006; 18(11): 1541 - 1548. [Abstract] [Full Text] [PDF]

				P. Otahal, T. D. Schell, S. C. Hutchinson, B. B. Knowles, and S. S. Tevethia Early Immunization Induces Persistent Tumor-Infiltrating CD8+ T Cells against an Immunodominant Epitope and Promotes Lifelong Control of Pancreatic Tumor Progression in SV40 Tumor Antigen Transgenic Mice. J. Immunol., September 1, 2006; 177(5): 3089 - 3099. [Abstract] [Full Text] [PDF]

				W. Wang, J. Epler, L. G. Salazar, and S. R. Riddell Recognition of Breast Cancer Cells by CD8+ Cytotoxic T-Cell Clones Specific for NY-BR-1. Cancer Res., July 1, 2006; 66(13): 6826 - 6833. [Abstract] [Full Text] [PDF]

				F. F. Shih, J. Racz, and P. M. Allen Differential MHC Class II Presentation of a Pathogenic Autoantigen during Health and Disease J. Immunol., March 15, 2006; 176(6): 3438 - 3448. [Abstract] [Full Text] [PDF]

				S. Yang, J. W. Hodge, D. W. Grosenbach, and J. Schlom Vaccines with Enhanced Costimulation Maintain High Avidity Memory CTL J. Immunol., September 15, 2005; 175(6): 3715 - 3723. [Abstract] [Full Text] [PDF]

				X. Martinez, H. T. C. Kreuwel, W. L. Redmond, R. Trenney, K. Hunter, H. Rosen, N. Sarvetnick, L. S. Wicker, and L. A. Sherman CD8+ T Cell Tolerance in Nonobese Diabetic Mice Is Restored by Insulin-Dependent Diabetes Resistance Alleles J. Immunol., August 1, 2005; 175(3): 1677 - 1685. [Abstract] [Full Text] [PDF]

				P. Otahal, S. C. Hutchinson, L. M. Mylin, M. J. Tevethia, S. S. Tevethia, and T. D. Schell Inefficient Cross-Presentation Limits the CD8+ T Cell Response to a Subdominant Tumor Antigen Epitope J. Immunol., July 15, 2005; 175(2): 700 - 712. [Abstract] [Full Text] [PDF]

				L. Steinaa, P. B. Rasmussen, A. M. Wegener, L. Sonderbye, D. R. Leach, J. Rygaard, S. Mouritsen, and A. M. Gautam Linked Foreign T-Cell Help Activates Self-Reactive CTL and Inhibits Tumor Growth J. Immunol., July 1, 2005; 175(1): 329 - 334. [Abstract] [Full Text] [PDF]

				P. Krebs, E. Scandella, B. Odermatt, and B. Ludewig Rapid Functional Exhaustion and Deletion of CTL following Immunization with Recombinant Adenovirus J. Immunol., April 15, 2005; 174(8): 4559 - 4566. [Abstract] [Full Text] [PDF]

				L. A. O'Mara, L. A. Norian, D. Kreamalmeyer, J. M. White, and P. M. Allen T Cell-Mediated Delay of Spontaneous Mammary Tumor Onset: Increased Efficacy with In Vivo versus In Vitro Activation J. Immunol., April 15, 2005; 174(8): 4662 - 4669. [Abstract] [Full Text] [PDF]

				P. Kleindienst, C. Wiethe, M. B. Lutz, and T. Brocker Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells J. Immunol., April 1, 2005; 174(7): 3941 - 3947. [Abstract] [Full Text] [PDF]

				M. A. Lyman, C. T. Nugent, K. L. Marquardt, J. A. Biggs, E. G. Pamer, and L. A. Sherman The Fate of Low Affinity Tumor-Specific CD8+ T Cells in Tumor-Bearing Mice J. Immunol., March 1, 2005; 174(5): 2563 - 2572. [Abstract] [Full Text] [PDF]

				W. L. Redmond, B. C. Marincek, and L. A. Sherman Distinct Requirements for Deletion versus Anergy during CD8 T Cell Peripheral Tolerance In Vivo J. Immunol., February 15, 2005; 174(4): 2046 - 2053. [Abstract] [Full Text] [PDF]

				C. W. Lawrence and T. J. Braciale Activation, Differentiation, and Migration of Naive Virus-Specific CD8+ T Cells during Pulmonary Influenza Virus Infection J. Immunol., July 15, 2004; 173(2): 1209 - 1218. [Abstract] [Full Text] [PDF]

				G. J. M. Webster, S. Reignat, D. Brown, G. S. Ogg, L. Jones, S. L. Seneviratne, R. Williams, G. Dusheiko, and A. Bertoletti Longitudinal Analysis of CD8+ T Cells Specific for Structural and Nonstructural Hepatitis B Virus Proteins in Patients with Chronic Hepatitis B: Implications for Immunotherapy J. Virol., June 1, 2004; 78(11): 5707 - 5719. [Abstract] [Full Text] [PDF]

				M. A. Lyman, S. Aung, J. A. Biggs, and L. A. Sherman A Spontaneously Arising Pancreatic Tumor Does Not Promote the Differentiation of Naive CD8+ T Lymphocytes into Effector CTL J. Immunol., June 1, 2004; 172(11): 6558 - 6567. [Abstract] [Full Text] [PDF]

				D. J. Morgan, C. T. Nugent, B. J. E. Raveney, and L. A. Sherman In a Transgenic Model of Spontaneous Autoimmune Diabetes, Expression of a Protective Class II MHC Molecule Results in Thymic Deletion of Diabetogenic CD8+ T Cells J. Immunol., January 15, 2004; 172(2): 1000 - 1008. [Abstract] [Full Text] [PDF]

				W. L. Redmond, J. Hernandez, and L. A. Sherman Deletion of Naive CD8 T Cells Requires Persistent Antigen and Is Not Programmed by an Initial Signal from the Tolerogenic APC J. Immunol., December 15, 2003; 171(12): 6349 - 6354. [Abstract] [Full Text] [PDF]

				K. Staveley-O'Carroll, T. D. Schell, M. Jimenez, L. M. Mylin, M. J. Tevethia, S. P. Schoenberger, and S. S. Tevethia In Vivo Ligation of CD40 Enhances Priming Against the Endogenous Tumor Antigen and Promotes CD8+ T Cell Effector Function in SV40 T Antigen Transgenic Mice J. Immunol., July 15, 2003; 171(2): 697 - 707. [Abstract] [Full Text] [PDF]

				A. K. Nowak, R. A. Lake, A. L. Marzo, B. Scott, W. R. Heath, E. J. Collins, J. A. Frelinger, and B. W. S. Robinson Induction of Tumor Cell Apoptosis In Vivo Increases Tumor Antigen Cross-Presentation, Cross-Priming Rather than Cross-Tolerizing Host Tumor-Specific CD8 T Cells J. Immunol., May 15, 2003; 170(10): 4905 - 4913. [Abstract] [Full Text] [PDF]

				C.-T. Huang, D. L. Huso, Z. Lu, T. Wang, G. Zhou, E. P. Kennedy, C. G. Drake, D. J. Morgan, L. A. Sherman, A. D. Higgins, et al. CD4+ T Cells Pass Through an Effector Phase During the Process of In Vivo Tolerance Induction J. Immunol., April 15, 2003; 170(8): 3945 - 3953. [Abstract] [Full Text] [PDF]

				L. Bonifaz, D. Bonnyay, K. Mahnke, M. Rivera, M. C. Nussenzweig, and R. M. Steinman Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance J. Exp. Med., December 16, 2002; 196(12): 1627 - 1638. [Abstract] [Full Text] [PDF]

				V. Vezys and L. Lefrancois Cutting Edge: Inflammatory Signals Drive Organ-Specific Autoimmunity to Normally Cross-Tolerizing Endogenous Antigen J. Immunol., December 15, 2002; 169(12): 6677 - 6680. [Abstract] [Full Text] [PDF]

				J. de Jersey, D. Carmignac, T. Barthlott, I. Robinson, and B. Stockinger Activation of CD8 T Cells by Antigen Expressed in the Pituitary Gland J. Immunol., December 15, 2002; 169(12): 6753 - 6759. [Abstract] [Full Text] [PDF]

				S. Lesage, S. B. Hartley, S. Akkaraju, J. Wilson, M. Townsend, and C. C. Goodnow Failure to Censor Forbidden Clones of CD4 T Cells in Autoimmune Diabetes J. Exp. Med., November 4, 2002; 196(9): 1175 - 1188. [Abstract] [Full Text] [PDF]

				C. Scheinecker, R. McHugh, E. M. Shevach, and R. N. Germain Constitutive Presentation of a Natural Tissue Autoantigen Exclusively by Dendritic Cells in the Draining Lymph Node J. Exp. Med., October 21, 2002; 196(8): 1079 - 1090. [Abstract] [Full Text] [PDF]

				J. Hernandez, S. Aung, K. Marquardt, and L. A. Sherman Uncoupling of Proliferative Potential and Gain of Effector Function by CD8+ T Cells Responding to Self-Antigens J. Exp. Med., August 5, 2002; 196(3): 323 - 333. [Abstract] [Full Text] [PDF]

				D. C. Tsitoura, V. P. Yeung, R. H. DeKruyff, and D. T. Umetsu Critical role of B cells in the development of T cell tolerance to aeroallergens Int. Immunol., June 1, 2002; 14(6): 659 - 667. [Abstract] [Full Text] [PDF]

				A. D. Higgins, M. A. Mihalyo, P. W. McGary, and A. J. Adler CD4 Cell Priming and Tolerization Are Differentially Programmed by APCs upon Initial Engagement J. Immunol., June 1, 2002; 168(11): 5573 - 5581. [Abstract] [Full Text] [PDF]

				L. T. Nguyen, A. R. Elford, K. Murakami, K. M. Garza, S. P. Schoenberger, B. Odermatt, D. E. Speiser, and P. S. Ohashi Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance J. Exp. Med., February 11, 2002; 195(4): 423 - 435. [Abstract] [Full Text] [PDF]

				T. D. Schell and S. S. Tevethia Control of Advanced Choroid Plexus Tumors in SV40 T Antigen Transgenic Mice Following Priming of Donor CD8+ T Lymphocytes by the Endogenous Tumor Antigen J. Immunol., December 15, 2001; 167(12): 6947 - 6956. [Abstract] [Full Text] [PDF]

				I. H. Frazer, R. D. Kluyver, G. R. Leggatt, H. Yang Guo, L. Dunn, O. White, C. Harris, A. Liem, and P. Lambert Tolerance or Immunity to a Tumor Antigen Expressed in Somatic Cells Can Be Determined by Systemic Proinflammatory Signals at the Time of First Antigen Exposure J. Immunol., December 1, 2001; 167(11): 6180 - 6187. [Abstract] [Full Text] [PDF]

				J. Hernandez, S. Aung, W. L. Redmond, and L. A. Sherman Phenotypic and Functional Analysis of Cd8+ T Cells Undergoing Peripheral Deletion in Response to Cross-Presentation of Self-Antigen J. Exp. Med., September 17, 2001; 194(6): 707 - 718. [Abstract] [Full Text] [PDF]

				D. Hawiger, K. Inaba, Y. Dorsett, M. Guo, K. Mahnke, M. Rivera, J. V. Ravetch, R. M. Steinman, and M. C. Nussenzweig Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo J. Exp. Med., September 17, 2001; 194(6): 769 - 780. [Abstract] [Full Text] [PDF]

				H. T. C. Kreuwel, J. A. Biggs, I. M. Pilip, E. G. Pamer, D. Lo, and L. A. Sherman Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice J. Immunol., July 15, 2001; 167(2): 1112 - 1117. [Abstract] [Full Text] [PDF]

				V. S. F. Chan, E. S. Cohen, T. Weissensteiner, K. S. E. Cheah, and H. C. Bodmer Chondrocyte antigen expression, immune response and susceptibility to arthritis Int. Immunol., April 1, 2001; 13(4): 421 - 429. [Abstract] [Full Text] [PDF]

				S. C. Eck and L. A. Turka Adoptive Transfer Enables Tumor Rejection Targeted against a Self-Antigen without the Induction of Autoimmunity Cancer Res., April 1, 2001; 61(7): 3077 - 3083. [Abstract] [Full Text]

				B. Ludewig, K. McCoy, M. Pericin, A. F. Ochsenbein, T. Dumrese, B. Odermatt, R. E. M. Toes, C. J. M. Melief, H. Hengartner, and R. M. Zinkernagel Rapid Peptide Turnover and Inefficient Presentation of Exogenous Antigen Critically Limit the Activation of Self-Reactive CTL by Dendritic Cells J. Immunol., March 15, 2001; 166(6): 3678 - 3687. [Abstract] [Full Text] [PDF]

				H. Ito, J. Kurtz, J. Shaffer, and M. Sykes CD4 T Cell-Mediated Alloresistance to Fully MHC-Mismatched Allogeneic Bone Marrow Engraftment Is Dependent on CD40-CD40 Ligand Interactions, and Lasting T Cell Tolerance Is Induced by Bone Marrow Transplantation with Initial Blockade of this Pathway J. Immunol., March 1, 2001; 166(5): 2970 - 2981. [Abstract] [Full Text] [PDF]

				C. Kurts, M. Cannarile, I. Klebba, and T. Brocker Cutting Edge: Dendritic Cells Are Sufficient to Cross-Present Self-Antigens to CD8 T Cells In Vivo J. Immunol., February 1, 2001; 166(3): 1439 - 1442. [Abstract] [Full Text] [PDF]

				P. Mukherjee, A. R. Ginardi, C. S. Madsen, C. J. Sterner, M. C. Adriance, M. J. Tevethia, and S. J. Gendler Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred J. Immunol., September 15, 2000; 165(6): 3451 - 3460. [Abstract] [Full Text] [PDF]

				T. D. Schell, B. B. Knowles, and S. S. Tevethia Sequential Loss of Cytotoxic T Lymphocyte Responses to Simian Virus 40 Large T Antigen Epitopes in T Antigen Transgenic Mice Developing Osteosarcomas Cancer Res., June 1, 2000; 60(11): 3002 - 3012. [Abstract] [Full Text] [PDF]

				T. A. Colella, T. N.J. Bullock, L. B. Russell, D. W. Mullins, W. W. Overwijk, C. J. Luckey, R. A. Pierce, N. P. Restifo, and V. H. Engelhard Self-Tolerance to the Murine Homologue of a Tyrosinase-Derived Melanoma Antigen: Implications for Tumor Immunotherapy J. Exp. Med., April 3, 2000; 191(7): 1221 - 1232. [Abstract] [Full Text] [PDF]

				B. Ludewig, A. F. Ochsenbein, B. Odermatt, D. Paulin, H. Hengartner, and R. M. Zinkernagel Immunotherapy with Dendritic Cells Directed against Tumor Antigens Shared with Normal Host Cells Results in Severe Autoimmune Disease J. Exp. Med., March 6, 2000; 191(5): 795 - 804. [Abstract] [Full Text] [PDF]

				T. N. J. Bullock, T. A. Colella, and V. H. Engelhard The Density of Peptides Displayed by Dendritic Cells Affects Immune Responses to Human Tyrosinase and gp100 in HLA-A2 Transgenic Mice J. Immunol., March 1, 2000; 164(5): 2354 - 2361. [Abstract] [Full Text] [PDF]

				Z. Lu, L. Yuan, X. Zhou, E. Sotomayor, H. I. Levitsky, and D. M. Pardoll Cd40-Independent Pathways of T Cell Help for Priming of Cd8+ Cytotoxic T Lymphocytes J. Exp. Med., February 7, 2000; 191(3): 541 - 550. [Abstract] [Full Text] [PDF]

				R. M. Steinman, S. Turley, I. Mellman, and K. Inaba The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic Cells J. Exp. Med., February 7, 2000; 191(3): 411 - 416. [Full Text] [PDF]

				A. J. Adler, C.-T. Huang, G. S. Yochum, D. W. Marsh, and D. M. Pardoll In Vivo CD4+ T Cell Tolerance Induction Versus Priming Is Independent of the Rate and Number of Cell Divisions J. Immunol., January 15, 2000; 164(2): 649 - 655. [Abstract] [Full Text] [PDF]

				C. T. Nugent, D. J. Morgan, J. A. Biggs, A. Ko, I. M. Pilip, E. G. Pamer, and L. A. Sherman Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas J. Immunol., January 1, 2000; 164(1): 191 - 200. [Abstract] [Full Text] [PDF]

				E. M. Sotomayor, I. Borrello, E. Tubb, J. P. Allison, and H. I. Levitsky In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance PNAS, September 28, 1999; 96(20): 11476 - 11481. [Abstract] [Full Text] [PDF]

				R. M. Steinman and M. C. Nussenzweig Inaugural Article: Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance PNAS, January 8, 2002; 99(1): 351 - 358. [Abstract] [Full Text] [PDF]