J. Exp. Med., Volume 189, Number 5, March 1, 1999 877-882

Peripheral Autoantigen Induces Regulatory T Cells that Prevent Autoimmunity

By Benedict Seddon and Don Mason

From the Medical Research Council Cellular Immunology Unit, Sir  William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom

Previous studies have shown that autoimmune thyroiditis can be induced in normal laboratory rats after thymectomy and split dose -irradiation. Development of disease can be prevented by reconstitution of PVG rats shortly after their final irradiation with either peripheral CD4⁺CD45RC T cells or CD4⁺CD8 thymocytes from syngeneic donors. Although the activity of both populations is known to depend on the activities of endogenously produced interleukin 4 and transforming growth factor , implying a common mechanism, the issue of antigen specificity of the cells involved has not yet been addressed. In this study, we show that the regulatory T cells that prevent autoimmune thyroiditis are generated in vivo only when the relevant autoantigen is also present. Peripheral CD4⁺ T cells, from rats whose thyroids were ablated in utero by treatment with ¹³¹I, were unable to prevent disease development upon adoptive transfer into thymectomized and irradiated recipients. This regulatory deficit is specific for thyroid autoimmunity, since CD4⁺ T cells from ¹³¹I-treated PVG.RT1^u rats were as effective as those from normal donors at preventing diabetes in thymectomized and irradiated PVG.RT1^u rats. Significantly, in contrast to the peripheral CD4⁺ T cells, CD4⁺CD8 thymocytes from ¹³¹I-treated PVG donors were still able to prevent thyroiditis upon adoptive transfer. Taken together, these data indicate that it is the peripheral autoantigen itself that stimulates the generation of the appropriate regulatory cells from thymic emigrant precursors.

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

This article has been cited by other articles:

• Guo, Z., Jang, M. H., Otani, K., Bai, Z., Umemoto, E., Matsumoto, M., Nishiyama, M., Yamasaki, M., Ueha, S., Matsushima, K., Hirata, T., Miyasaka, M. (2008). CD4+CD25+ regulatory T cells in the small intestinal lamina propria show an effector/memory phenotype. Int Immunol 20: 307-315 [Abstract] [Full Text]  
• Larkin, J. III, Rankin, A. L., Picca, C. C., Riley, M. P., Jenks, S. A., Sant, A. J., Caton, A. J. (2008). CD4+CD25+ Regulatory T Cell Repertoire Formation Shaped by Differential Presentation of Peptides from a Self-Antigen. J. Immunol. 180: 2149-2157 [Abstract] [Full Text]  
• Antons, A. K., Wang, R., Oswald-Richter, K., Tseng, M., Arendt, C. W., Kalams, S. A., Unutmaz, D. (2008). Naive Precursors of Human Regulatory T Cells Require FoxP3 for Suppression and Are Susceptible to HIV Infection. J. Immunol. 180: 764-773 [Abstract] [Full Text]  
• Liu, M.-F., Lin, L.-H., Weng, C.-T., Weng, M.-Y. (2008). Decreased CD4+CD25+bright T cells in peripheral blood of patients with primary Sjogren's syndrome. Lupus 17: 34-39 [Abstract]  
• Li, S., Gowans, E. J., Chougnet, C., Plebanski, M., Dittmer, U. (2008). Natural Regulatory T Cells and Persistent Viral Infection. J. Virol. 82: 21-30 [Full Text]  
• Kapp, J. A., Honjo, K., Kapp, L. M., Goldsmith, K., Bucy, R. P. (2007). Antigen, in the Presence of TGF-beta, Induces Up-Regulation of FoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses. J. Immunol. 179: 2105-2114 [Abstract] [Full Text]  
• Golshayan, D., Jiang, S., Tsang, J., Garin, M. I., Mottet, C., Lechler, R. I. (2007). In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood 109: 827-835 [Abstract] [Full Text]  
• Tiittanen, M., Huupponen, J. T., Knip, M., Vaarala, O. (2006). Insulin Treatment in Patients With Type 1 Diabetes Induces Upregulation of Regulatory T-Cell Markers in Peripheral Blood Mononuclear Cells Stimulated With Insulin In Vitro. Diabetes 55: 3446-3454 [Abstract] [Full Text]  
• Toda, A., Piccirillo, C. A. (2006). Development and function of naturally occurring CD4+CD25+ regulatory T cells. J. Leukoc. Biol. 80: 458-470 [Abstract] [Full Text]  
• Wang, R.-F. (2006). Regulatory T cells and toll-like receptors in cancer therapy.. Cancer Res. 66: 4987-4990 [Abstract] [Full Text]  
• Yu, S., Maiti, P. K., Dyson, M., Jain, R., Braley-Mullen, H. (2006). B cell-deficient NOD.H-2h4 mice have CD4+CD25+ T regulatory cells that inhibit the development of spontaneous autoimmune thyroiditis. J. Exp. Med. 203: 349-358 [Abstract] [Full Text]  
• Setiady, Y. Y., Ohno, K., Samy, E. T., Bagavant, H., Qiao, H., Sharp, C., She, J. X., Tung, K. S. K. (2006). Physiologic self antigens rapidly capacitate autoimmune disease-specific polyclonal CD4+CD25+ regulatory T cells. Blood 107: 1056-1062 [Abstract] [Full Text]  
• Kitade, H., Kawai, M., Rutgeerts, O., Landuyt, W., Waer, M., Mathieu, C., Pirenne, J. (2005). Early Presence of Regulatory Cells in Transplanted Rats Rendered Tolerant by Donor-Specific Blood Transfusion. J. Immunol. 175: 4963-4970 [Abstract] [Full Text]  
• Huang, X., Zhu, J., Yang, Y. (2005). Protection against Autoimmunity in Nonlymphopenic Hosts by CD4+CD25+ Regulatory T Cells Is Antigen-Specific and Requires IL-10 and TGF-{beta}. J. Immunol. 175: 4283-4291 [Abstract] [Full Text]  
• Samy, E. T., Parker, L. A., Sharp, C. P., Tung, K. S.K. (2005). Continuous control of autoimmune disease by antigen-dependent polyclonal CD4+CD25+ regulatory T cells in the regional lymph node. J. Exp. Med. 202: 771-781 [Abstract] [Full Text]  
• Masteller, E. L., Warner, M. R., Tang, Q., Tarbell, K. V., McDevitt, H., Bluestone, J. A. (2005). Expansion of Functional Endogenous Antigen-Specific CD4+CD25+ Regulatory T Cells from Nonobese Diabetic Mice. J. Immunol. 175: 3053-3059 [Abstract] [Full Text]  
• Bagavant, H., Tung, K. S. K. (2005). Failure of CD25+ T Cells from Lupus-Prone Mice to Suppress Lupus Glomerulonephritis and Sialoadenitis. J. Immunol. 175: 944-950 [Abstract] [Full Text]  
• Nardelli, D. T., Cloute, J. P., Luk, K. H. K., Torrealba, J., Warner, T. F., Callister, S. M., Schell, R. F. (2005). CD4+ CD25+ T Cells Prevent Arthritis Associated with Borrelia Vaccination and Infection. CVI 12: 786-792 [Abstract] [Full Text]  
• Verginis, P., Li, H. S., Carayanniotis, G. (2005). Tolerogenic Semimature Dendritic Cells Suppress Experimental Autoimmune Thyroiditis by Activation of Thyroglobulin-Specific CD4+CD25+ T Cells. J. Immunol. 174: 7433-7439 [Abstract] [Full Text]  
• Walker, M. R., Carson, B. D., Nepom, G. T., Ziegler, S. F., Buckner, J. H. (2005). De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. Proc. Natl. Acad. Sci. USA 102: 4103-4108 [Abstract] [Full Text]  
• Nishikawa, H., Kato, T., Tawara, I., Saito, K., Ikeda, H., Kuribayashi, K., Allen, P. M., Schreiber, R. D., Sakaguchi, S., Old, L. J., Shiku, H. (2005). Definition of target antigens for naturally occurring CD4+ CD25+ regulatory T cells. J. Exp. Med. 201: 681-686 [Abstract] [Full Text]  
• Wang, H. Y., Peng, G., Guo, Z., Shevach, E. M., Wang, R.-F. (2005). Recognition of a New ARTC1 Peptide Ligand Uniquely Expressed in Tumor Cells by Antigen-Specific CD4+ Regulatory T Cells. J. Immunol. 174: 2661-2670 [Abstract] [Full Text]  
• Xystrakis, E., Dejean, A. S., Bernard, I., Druet, P., Liblau, R., Gonzalez-Dunia, D., Saoudi, A. (2004). Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation. Blood 104: 3294-3301 [Abstract] [Full Text]  
• Sarween, N., Chodos, A., Raykundalia, C., Khan, M., Abbas, A. K., Walker, L. S. K. (2004). CD4+CD25+ Cells Controlling a Pathogenic CD4 Response Inhibit Cytokine Differentiation, CXCR-3 Expression, and Tissue Invasion. J. Immunol. 173: 2942-2951 [Abstract] [Full Text]  
• Lerman, M. A., Larkin, J. III, Cozzo, C., Jordan, M. S., Caton, A. J. (2004). CD4+ CD25+ Regulatory T Cell Repertoire Formation in Response to Varying Expression of a neo-Self-Antigen. J. Immunol. 173: 236-244 [Abstract] [Full Text]  
• Tanchot, C., Vasseur, F., Pontoux, C., Garcia, C., Sarukhan, A. (2004). Immune Regulation by Self-Reactive T Cells is Antigen Specific. J. Immunol. 172: 4285-4291 [Abstract] [Full Text]  
• Min, B., Foucras, G., Meier-Schellersheim, M., Paul, W. E. (2004). Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire. Proc. Natl. Acad. Sci. USA 101: 3874-3879 [Abstract] [Full Text]  
• Martin, B., Banz, A., Bienvenu, B., Cordier, C., Dautigny, N., Becourt, C., Lucas, B. (2004). Suppression of CD4+ T Lymphocyte Effector Functions by CD4+CD25+ Cells In Vivo. J. Immunol. 172: 3391-3398 [Abstract] [Full Text]  
• Cozzo, C., Larkin, J. III, Caton, A. J. (2003). Cutting Edge: Self-Peptides Drive the Peripheral Expansion of CD4+CD25+ Regulatory T Cells. J. Immunol. 171: 5678-5682 [Abstract] [Full Text]  
• Omer, F. M., de Souza, J. B., Riley, E. M. (2003). Differential Induction of TGF-{beta} Regulates Proinflammatory Cytokine Production and Determines the Outcome of Lethal and Nonlethal Plasmodium yoelii Infections. J. Immunol. 171: 5430-5436 [Abstract] [Full Text]  
• Tang, Q., Henriksen, K. J., Boden, E. K., Tooley, A. J., Ye, J., Subudhi, S. K., Zheng, X. X., Strom, T. B., Bluestone, J. A. (2003). Cutting Edge: CD28 Controls Peripheral Homeostasis of CD4+CD25+ Regulatory T Cells. J. Immunol. 171: 3348-3352 [Abstract] [Full Text]  
• Jiang, S., Camara, N., Lombardi, G., Lechler, R. I. (2003). Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. Blood 102: 2180-2186 [Abstract] [Full Text]  
• Fisson, S., Darrasse-Jeze, G., Litvinova, E., Septier, F., Klatzmann, D., Liblau, R., Salomon, B. L. (2003). Continuous Activation of Autoreactive CD4+ CD25+ Regulatory T Cells in the Steady State. J. Exp. Med. 198: 737-746 [Abstract] [Full Text]  
• Walker, L. S.K., Chodos, A., Eggena, M., Dooms, H., Abbas, A. K. (2003). Antigen-dependent Proliferation of CD4+ CD25+ Regulatory T Cells In Vivo. J. Exp. Med. 198: 249-258 [Abstract] [Full Text]  
• Chen, C., Lee, W.-H., Yun, P., Snow, P., Liu, C.-P. (2003). Induction of Autoantigen-Specific Th2 and Tr1 Regulatory T Cells and Modulation of Autoimmune Diabetes. J. Immunol. 171: 733-744 [Abstract] [Full Text]  
• Hug, A., Korporal, M., Schroder, I., Haas, J., Glatz, K., Storch-Hagenlocher, B., Wildemann, B. (2003). Thymic Export Function and T Cell Homeostasis in Patients with Relapsing Remitting Multiple Sclerosis. J. Immunol. 171: 432-437 [Abstract] [Full Text]  
• Mahnke, K., Qian, Y., Knop, J., Enk, A. H. (2003). Induction of CD4+/CD25+ regulatory T cells by targeting of antigens to immature dendritic cells. Blood 101: 4862-4869 [Abstract] [Full Text]  
• Boyle, L. H., Hill Gaston, J. S. (2003). Breaking the rules: the unconventional recognition of HLA-B27 by CD4+ T lymphocytes as an insight into the pathogenesis of the spondyloarthropathies. Rheumatology (Oxford) 42: 404-412 [Abstract] [Full Text]  
• Kipnis, J., Mizrahi, T., Hauben, E., Shaked, I., Shevach, E., Schwartz, M. (2002). Neuroprotective autoimmunity: Naturally occurring CD4+CD25+ regulatory T cells suppress the ability to withstand injury to the central nervous system. Proc. Natl. Acad. Sci. USA 99: 15620-15625 [Abstract] [Full Text]  
• Ramanathan, S., Bihoreau, M.-T., Paterson, A. D., Marandi, L., Gauguier, D., Poussier, P. (2002). Thymectomy and Radiation-Induced Type 1 Diabetes in Nonlymphopenic BB Rats. Diabetes 51: 2975-2981 [Abstract] [Full Text]  
• Kullberg, M. C., Jankovic, D., Gorelick, P. L., Caspar, P., Letterio, J. J., Cheever, A. W., Sher, A. (2002). Bacteria-triggered CD4+ T Regulatory Cells Suppress Helicobacter hepaticus-induced Colitis. J. Exp. Med. 196: 505-515 [Abstract] [Full Text]  
• Sfondrini, L., Besusso, D., Zoia, M. T., Rodolfo, M., Invernizzi, A. M., Taniguchi, M., Nakayama, T., Colombo, M. P., Menard, S., Balsari, A. (2002). Absence of the CD1 Molecule Up-Regulates Antitumor Activity Induced by CpG Oligodeoxynucleotides in Mice. J. Immunol. 169: 151-158 [Abstract] [Full Text]  
• Singh, R. R., Ebling, F. M., Albuquerque, D. A., Saxena, V., Kumar, V., Giannini, E. H., Marion, T. N., Finkelman, F. D., Hahn, B. H. (2002). Induction of Autoantibody Production Is Limited in Nonautoimmune Mice. J. Immunol. 169: 587-594 [Abstract] [Full Text]  
• Hori, S., Haury, M., Coutinho, A., Demengeot, J. (2002). Specificity requirements for selection and effector functions of CD25+4+ regulatory T cells in anti-myelin basic protein T cell receptor transgenic mice. Proc. Natl. Acad. Sci. USA 99: 8213-8218 [Abstract] [Full Text]  
• Kawahata, K., Misaki, Y., Yamauchi, M., Tsunekawa, S., Setoguchi, K., Miyazaki, J.-i., Yamamoto, K. (2002). Generation of CD4+CD25+ Regulatory T Cells from Autoreactive T Cells Simultaneously with Their Negative Selection in the Thymus and from Nonautoreactive T Cells by Endogenous TCR Expression. J. Immunol. 168: 4399-4405 [Abstract] [Full Text]  
• Romagnoli, P., Hudrisier, D., van Meerwijk, J. P. M. (2002). Preferential Recognition of Self Antigens Despite Normal Thymic Deletion of CD4+CD25+ Regulatory T Cells. J. Immunol. 168: 1644-1648 [Abstract] [Full Text]  
• Pacholczyk, R., Kraj, P., Ignatowicz, L. (2002). Peptide Specificity of Thymic Selection of CD4+CD25+ T Cells. J. Immunol. 168: 613-620 [Abstract] [Full Text]  
• Pack, C. D., Cestra, A. E., Min, B., Legge, K. L., Li, L., Caprio-Young, J. C., Bell, J. J., Gregg, R. K., Zaghouani, H. (2001). Neonatal Exposure to Antigen Primes the Immune System to Develop Responses in Various Lymphoid Organs and Promotes Bystander Regulation of Diverse T Cell Specificities. J. Immunol. 167: 4187-4195 [Abstract] [Full Text]  
• Bensinger, S. J., Bandeira, A., Jordan, M. S., Caton, A. J., Laufer, T. M. (2001). Major Histocompatibility Complex Class II-positive Cortical Epithelium Mediates the Selection of CD4+25+ Immunoregulatory T Cells. J. Exp. Med. 194: 427-438 [Abstract] [Full Text]  
• Weissert, R., de Graaf, K. L., Storch, M. K., Barth, S., Linington, C., Lassmann, H., Olsson, T. (2001). MHC Class II-Regulated Central Nervous System Autoaggression and T Cell Responses in Peripheral Lymphoid Tissues Are Dissociated in Myelin Oligodendrocyte Glycoprotein-Induced Experimental Autoimmune Encephalomyelitis. J. Immunol. 166: 7588-7599 [Abstract] [Full Text]  
• Shevach, E. M. (2001). Certified Professionals: CD4+CD25+ Suppressor T Cells. J. Exp. Med. 193: F41-F46 [Full Text]  
• Jonuleit, H., Schmitt, E., Stassen, M., Tuettenberg, A., Knop, J., Enk, A. H. (2001). Identification and Functional Characterization of Human CD4+CD25+ T Cells with Regulatory Properties Isolated from Peripheral Blood. J. Exp. Med. 193: 1285-1294 [Abstract] [Full Text]  
• Dieckmann, D., Plottner, H., Berchtold, S., Berger, T., Schuler, G. (2001). Ex Vivo Isolation and Characterization of CD4+CD25+ T Cells with Regulatory Properties from Human Blood. J. Exp. Med. 193: 1303-1310 [Abstract] [Full Text]  
• Yamamoto, A. M., Chernajovsky, Y., Lepault, F., Podhajcer, O., Feldmann, M., Bach, J.-F., Chatenoud, L. (2001). The Activity of Immunoregulatory T Cells Mediating Active Tolerance Is Potentiated in Nonobese Diabetic Mice by an IL-4-Based Retroviral Gene Therapy. J. Immunol. 166: 4973-4980 [Abstract] [Full Text]  
• Lindsey, J. W., Jin, R. (2000). Immune regulatory effects of central nervous system antigens in culture. Int Immunol 12: 1605-1612 [Abstract] [Full Text]  
• Zanelli, E., Breedveld, F. C., de Vries, R. R. P. (2000). HLA association with autoimmune disease: a failure to protect?. Rheumatology (Oxford) 39: 1060-1066 [Abstract] [Full Text]  
• Stephens, L. A., Mason, D. (2000). CD25 Is a Marker for CD4+ Thymocytes That Prevent Autoimmune Diabetes in Rats, But Peripheral T Cells with This Function Are Found in Both CD25+ and CD25- Subpopulations. J. Immunol. 165: 3105-3110 [Abstract] [Full Text]  
• Legge, K. L., Min, B., Bell, J. J., Caprio, J. C., Li, L., Gregg, R. K., Zaghouani, H. (2000). Coupling of Peripheral Tolerance to Endogenous Interleukin 10 Promotes Effective Modulation of Myelin-activated T Cells and Ameliorates Experimental Allergic Encephalomyelitis. J. Exp. Med. 191: 2039-2052 [Abstract] [Full Text]  
• Olivares-Villagomez, D., Wensky, A. K., Wang, Y., Lafaille, J. J. (2000). Repertoire Requirements of CD4+ T Cells That Prevent Spontaneous Autoimmune Encephalomyelitis. J. Immunol. 164: 5499-5507 [Abstract] [Full Text]  
• Garza, K. M., Agersborg, S. S., Baker, E., Tung, K. S. K. (2000). Persistence of Physiological Self Antigen Is Required for the Regulation of Self Tolerance. J. Immunol. 164: 3982-3989 [Abstract] [Full Text]  
• Thornton, A. M., Shevach, E. M. (2000). Suppressor Effector Function of CD4+CD25+ Immunoregulatory T Cells Is Antigen Nonspecific. J. Immunol. 164: 183-190 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS