Regulatory lymphocytes: Antigen-induced regulatory T cells in autoimmunity

The ultimate goal of any treatment for autoimmune diseases is antigen- and/or site-specific suppression of pathology. Autoaggressive lymphocytes need to be eliminated or controlled to prevent tissue damage and halt the progression of clinical disease. Strong evidence is emerging that the induction of regulatory T (TReg) cells by autoantigens can suppress disease, even if the primary, initiating autoantigens are unknown and if inflammation is progressive. An advantage of these autoreactive TReg cells is their ability to act as bystander suppressors and dampen inflammation in a site-specific manner in response to cognate antigen expressed locally by affected tissues. In this review, we consider the nature and function of such antigen-specific TReg cells, and strategies for their therapeutic induction are discussed.

[1]  M. V. von Herrath,et al.  Plasmid Vaccination with Insulin B Chain Prevents Autoimmune Diabetes in Nonobese Diabetic Mice1 , 2001, The Journal of Immunology.

[2]  M. V. von Herrath,et al.  Tolerance induction with agonist peptides recognized by autoaggressive lymphocytes is transient: therapeutic potential for type 1 diabetes is limited and depends on time-point of administration, choice of epitope and adjuvant. , 2001, Journal of autoimmunity.

[3]  S. Miller,et al.  Theiler's Virus‐Mediated Autoimmunity , 2002, Annals of the New York Academy of Sciences.

[4]  G. Mayrhofer,et al.  Ia antigens in rat kidney, with special reference to their expression in tubular epithelium , 1983, The Journal of experimental medicine.

[5]  P. Allen,et al.  Induction of T-cell anergy by altered T-cell-receptor ligand on live antigen-presenting cells , 1993, Nature.

[6]  Disabling an integral CTL epitope allows suppression of autoimmune diabetes by intranasal proinsulin peptide , 2003 .

[7]  S. Baekkeskov,et al.  Endogenous expression levels of autoantigens influence success or failure of DNA immunizations to prevent type 1 diabetes: addition of IL‐4 increases safety , 2002, European journal of immunology.

[8]  H. Weiner,et al.  Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. , 1991 .

[9]  H. Macdonald,et al.  The Early IL-4 Response to Leishmania major and the Resulting Th2 Cell Maturation Steering Progressive Disease in BALB/c Mice Are Subject to the Control of Regulatory CD4+CD25+ T Cells1 , 2002, The Journal of Immunology.

[10]  D. Mason,et al.  Intrathymic expression of genes involved in organ specific autoimmune disease. , 1998, Journal of autoimmunity.

[11]  M. Toda,et al.  Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. , 1998, International immunology.

[12]  R. Baggott.  DISEASE , 1947, Social Policy & Administration.

[13]  R. Schwartz,et al.  Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. , 1987, Journal of immunology.

[14]  C. Thivolet,et al.  Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. , 1994, Journal of autoimmunity.

[15]  D. Wegmann,et al.  Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23). , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  L. Harrison,et al.  Aerosol Insulin Induces Regulatory CD8 γδ T Cells That Prevent Murine Insulin-dependent Diabetes , 1996, The Journal of experimental medicine.

[17]  H. Weiner,et al.  Epitopes of myelin basic protein that trigger TGF-beta release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression. , 1993, Journal of immunology.

[18]  T. Mak,et al.  Immunologic Self-Tolerance Maintained by Cd25+Cd4+Regulatory T Cells Constitutively Expressing Cytotoxic T Lymphocyte–Associated Antigen 4 , 2000, The Journal of experimental medicine.

[19]  R. de Waal Malefyt,et al.  IFN-α and IL-10 Induce the Differentiation of Human Type 1 T Regulatory Cells1 , 2001, The Journal of Immunology.

[20]  Klaus-Armin Nave,et al.  Shaping of the autoreactive T-cell repertoire by a splice variant of self protein expressed in thymic epithelial cells , 2000, Nature Medicine.

[21]  S. Tonegawa,et al.  Evidence for a differential avidity model of T cell selection in the thymus , 1994, Cell.

[22]  J. Bach.  Regulatory lymphocytes: Regulatory T cells under scrutiny , 2003, Nature Reviews Immunology.

[23]  J. Rygaard,et al.  Immune-deficient animals in biomedical research , 1987 .

[24]  R. Steinman.  Inaugural Article : avoiding horror autotoxicus. The importance of dendritic cells in peripheral T cell tolerance , 2002 .

[25]  A. Signore,et al.  NOD mouse colonies around the world--recent facts and figures. , 1993, Immunology today.

[26]  P. Fontoura,et al.  Combination of gene delivery and DNA vaccination to protect from and reverse Th1 autoimmune disease via deviation to the Th2 pathway. , 2001, Immunity.

[27]  H. Weiner,et al.  Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. , 1996, The Journal of clinical investigation.

[28]  A. Mowat,et al.  Expanding dendritic cells in vivo enhances the induction of oral tolerance. , 1998, Journal of immunology.

[29]  D. Wraith,et al.  Selection and fine-tuning of the autoimmune T-cell repertoire , 2002, Nature Reviews Immunology.

[30]  A. Hänninen,et al.  gd T cells as mediators of mucosal tolerance: the autoimmune diabetes model , 2000 .

[31]  K. Mills,et al.  Pathogen-specific regulatory T cells provoke a shift in the Th1/Th2 paradigm in immunity to infectious diseases. , 2002, Trends in immunology.

[32]  E. Shevach,et al.  CD4+CD25+ T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. , 1998, Journal of immunology.

[33]  J. Revillard,et al.  Murine enterocytes can present soluble antigen to specific class II‐restricted CD4+ T cells , 1989, European journal of immunology.

[34]  L. Mayer,et al.  Evidence for function of Ia molecules on gut epithelial cells in man , 1987, The Journal of experimental medicine.

[35]  Alf Hamann,et al.  Expression of the integrin αEβ7 identifies unique subsets of CD25+ as well as CD25− regulatory T cells , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[36]  S. Arbogast,et al.  Molecular mimicry as a therapeutic approach for an autoimmune disease: oral treatment of uveitis-patients with an MHC-peptide crossreactive with autoantigen--first results. , 1997, Immunology letters.

[37]  M. V. von Herrath,et al.  DNA immunization to prevent autoimmune diabetes. , 1999, The Journal of clinical investigation.

[38]  L. Harrison,et al.  Transient blockade of CD40 ligand dissociates pathogenic from protective mucosal immunity. , 2002, The Journal of clinical investigation.

[39]  S. Hauser,et al.  Late Complications of Immune Deviation Therapy in a Nonhuman Primate , 1996, Science.

[40]  H. Weiner,et al.  Oral tolerance: mechanisms and therapeutic applications. , 1999, Advances in immunology.

[41]  Y. Belkaid,et al.  CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity , 2002, Nature.

[42]  H. Weiner,et al.  Induction and mechanism of action of transforming growth factor‐β‐secreting Th3 regulatory cells , 2001, Immunological reviews.

[43]  S. Sakaguchi,et al.  Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation , 1996, The Journal of experimental medicine.

[44]  Sayuri Yamazaki,et al.  Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance , 2001, Immunological reviews.

[45]  D. Wraith,et al.  Inhibition of experimental autoimmune encephalomyelitis by inhalation but not oral administration of the encephalitogenic peptide: influence of MHC binding affinity. , 1993, International immunology.

[46]  M. Burdick,et al.  Insulin B-chain reactive CD4+ regulatory T-cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells. , 1999, Diabetes.

[47]  L. Kaer,et al.  The natural killer T-cell ligand α-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice , 2001, Nature Medicine.

[48]  F. Marincola,et al.  Inhibition of cytolytic T lymphocyte proliferation by autologous CD4+/CD25+ regulatory T cells in a colorectal carcinoma patient is mediated by transforming growth factor-beta. , 2002, Cancer research.

[49]  R. Steinman,et al.  Antigen-bearing immature dendritic cells induce peptide-specific CD8(+) regulatory T cells in vivo in humans. , 2002, Blood.

[50]  R. Lechler,et al.  The contributions of T‐cell anergy to peripheral T‐cell tolerance , 2001, Immunology.

[51]  N. Kadowaki,et al.  Reciprocal control of T helper cell and dendritic cell differentiation. , 1999, Science.

[52]  H. Weiner,et al.  Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[53]  R. Schwartz,et al.  Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. , 1999, Journal of immunology.

[54]  J. Petersen,et al.  Autoreactive CD4+ T cells protect from autoimmune diabetes via bystander suppression using the IL-4/Stat6 pathway. , 1999, Immunity.

[55]  D. Hafler,et al.  Antigen-specific therapy for autoimmune disease. , 2000, Current opinion in immunology.

[56]  D. Wraith,et al.  Intranasal peptide-induced peripheral tolerance: the role of IL-10 in regulatory T cell function within the context of experimental autoimmune encephalomyelitis. , 2002, Veterinary immunology and immunopathology.

[57]  G. Freeman,et al.  CD4+CD25high Regulatory Cells in Human Peripheral Blood1 , 2001, The Journal of Immunology.

[58]  A. Khoruts,et al.  Generation of Anergic and Potentially Immunoregulatory CD25+CD4 T Cells In Vivo After Induction of Peripheral Tolerance with Intravenous or Oral Antigen1 , 2001, The Journal of Immunology.

[59]  P. Matzinger.  Tolerance, danger, and the extended family. , 1994, Annual review of immunology.

[60]  B. Hall,et al.  Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells , 1985, The Journal of experimental medicine.

[61]  T. Sugie,et al.  Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[62]  M. Jordan.  Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide , 2001, Nature Immunology.

[63]  G. Trinchieri.  Regulatory Role of T Cells Producing both Interferon γ and Interleukin 10 in Persistent Infection , 2001, The Journal of experimental medicine.

[64]  深浦彦彰.  Induction of Circulating Myelin Basic Protein and Proteolipid Protein-specific Transforming-Growth Factor-β1-secreting Th3 T Cells by Oral Administration of Myelin in Multiple Sclerosis Patients(ミエリン蛋白を経口投与された多発性硬化症患者におけるミエリン塩基性蛋白およびプロテオリピッドプロテイン特異的TGF-β1分泌性Th3T細胞の促進) , 1997 .

[65]  H. Weiner,et al.  Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. , 1993, Science.

[66]  H. Weiner,et al.  Effects of oral administration of type II collagen on rheumatoid arthritis. , 1993, Science.

[67]  D. Zélénika,et al.  Regulatory T Cells Overexpress a Subset of Th2 Gene Transcripts1 , 2002, The Journal of Immunology.

[68]  B. Zweiman,et al.  Isolation of myelin basic protein-reactive T-cell lines from normal human blood. , 1983, Cellular immunology.

[69]  D. Mason,et al.  The Physiological Role of Regulatory T Cells in the Prevention of Autoimmunity: the Function of the Thymus in the Generation of the Regulatory T Cell Subset , 1996, Immunological reviews.

[70]  A. Abbas,et al.  Life and death in effector T cells , 2002, Nature Immunology.

[71]  J. Bach,et al.  The effect of infections on susceptibility to autoimmune and allergic diseases. , 2002, The New England journal of medicine.

[72]  L. Klein,et al.  Origin of regulatory T cells with known specificity for antigen , 2002, Nature Immunology.

[73]  F. Finkelman,et al.  Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23. , 2002, The Journal of clinical investigation.

[74]  D. Loh,et al.  Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. , 1994, Immunity.

[75]  H. Weiner.  The mucosal milieu creates tolerogenic dendritic cells and TR1 and TH3 regulatory cells , 2001, Nature Immunology.

[76]  Christopher Anderson,et al.  More questions than answers , 1991, Nature.

[77]  M. Gilliet,et al.  Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells , 2002, The Journal of experimental medicine.

[78]  H. Waldmann,et al.  Induction of tolerance in peripheral T cells with monoclonal antibodies , 1990, European journal of immunology.

[79]  Scott N. Mueller,et al.  The CD8α+ Dendritic Cell Is Responsible for Inducing Peripheral Self-Tolerance to Tissue-associated Antigens , 2002, The Journal of experimental medicine.

[80]  H. Weiner,et al.  Activation of CD25+CD4+ Regulatory T Cells by Oral Antigen Administration1 , 2001, The Journal of Immunology.

[81]  G. Schönrich,et al.  Multiple levels of peripheral tolerance. , 1993, Immunology today.

[82]  C. Boitard,et al.  T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice , 1989, The Journal of experimental medicine.

[83]  D. Keskin,et al.  Potential Regulatory Function of Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase , 2002, Science.

[84]  F. Ruscetti,et al.  Induction of CD4+ T cell alloantigen-specific hyporesponsiveness by IL-10 and TGF-beta. , 1999, Journal of immunology.

[85]  G. Eisenbarth,et al.  Enumerating autoreactive T cells in peripheral blood: a big step in diabetes prediction. , 2003, The Journal of clinical investigation.

[86]  D. Kioussis,et al.  "Infectious" transplantation tolerance , 1993, Science.

[87]  H. Mcdevitt,et al.  CD4+ T Cells from Glutamic Acid Decarboxylase (GAD)65-specific T Cell Receptor Transgenic Mice Are Not Diabetogenic and Can Delay Diabetes Transfer , 2002, The Journal of experimental medicine.

[88]  Michel C. Nussenzweig,et al.  Avoiding horror autotoxicus: The importance of dendritic cells in peripheral T cell tolerance , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[89]  A. T. N. Group,et al.  No effect of oral insulin on residual beta-cell function in recent-onset Type I diabetes (the IMDIAB VII) , 2000, Diabetologia.

[90]  Andrew W. Liu,et al.  Detection of GAD65-specific T-cells by major histocompatibility complex class II tetramers in type 1 diabetic patients and at-risk subjects. , 2002, Diabetes.

[91]  J. Killestein.  Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. , 2002, The New England journal of medicine.

[92]  J. Lafaille,et al.  Repertoire Requirements of CD4+ T Cells That Prevent Spontaneous Autoimmune Encephalomyelitis1 , 2000, The Journal of Immunology.

[93]  R. Tisch,et al.  Plasmid DNAs Encoding Insulin and Glutamic Acid Decarboxylase 65 Have Distinct Effects on the Progression of Autoimmune Diabetes in Nonobese Diabetic Mice1 , 2001, The Journal of Immunology.

[94]  L. Degroot,et al.  Induction of oral tolerance in human autoimmune thyroid disease. , 1998, Thyroid : official journal of the American Thyroid Association.

[95]  H. Weiner,et al.  Mechanisms of Oral Tolerance by MHC Peptides , 1996, Annals of the New York Academy of Sciences.

[96]  J. Kapp,et al.  Gamma delta T lymphocytes regulate the induction and maintenance of oral tolerance. , 1997, Journal of immunology.

[97]  B. Hall,et al.  Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action , 1990, The Journal of experimental medicine.

[98]  Y. Koga,et al.  Development and cytolytic function of intestinal intraepithelial T lymphocytes in antigen‐minimized mice , 1996, Immunology.

[99]  E. Sercarz,et al.  Induction or protection from experimental autoimmune encephalomyelitis depends on the cytokine secretion profile of TCR peptide-specific regulatory CD4 T cells. , 1998, Journal of immunology.

[100]  J. D. de Vries,et al.  Interleukin-10 induces a long-term antigen-specific anergic state in human CD4+ T cells , 1996, The Journal of experimental medicine.

[101]  J. G. Michael,et al.  Orally inducible immune unresponsiveness is abrogated by IFN-gamma treatment. , 1990, Journal of immunology.

[102]  S. Husby,et al.  Suppression of the immune response by nasal immunization. , 1994, Clinical immunology and immunopathology.

[103]  Vladimir Brusic,et al.  A Peptide-binding Motif for I-Ag7, the Class II Major Histocompatibility Complex (MHC) Molecule of NOD and Biozzi AB/H Mice , 1997, The Journal of experimental medicine.

[104]  J. Satoh,et al.  [Immunotherapy of insulin-dependent diabetes mellitus]. , 1991, Nihon rinsho. Japanese journal of clinical medicine.

[105]  H. Fujita,et al.  Induction of tolerance in influenza virus-immune T lymphocyte clones with synthetic peptides of influenza hemagglutinin , 1983, The Journal of experimental medicine.

[106]  D. Mason,et al.  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− Subpopulations1 , 2000, The Journal of Immunology.

[107]  R. Zinkernagel,et al.  Induction and Exhaustion of Lymphocytic Choriomeningitis Virus–specific Cytotoxic T Lymphocytes Visualized Using Soluble Tetrameric Major Histocompatibility Complex Class I–Peptide Complexes , 1998, The Journal of experimental medicine.

[108]  L. Harrison,et al.  Mucosal antigen primes diabetogenic cytotoxic T-lymphocytes regardless of dose or delivery route. , 2001, Diabetes.

[109]  M. Russo,et al.  Anti-γδ T cell antibody blocks the induction and maintenance of oral tolerance to ovalbumin in mice , 1995 .

[110]  J. Petersen,et al.  Insulin in oral immune "tolerance": a one-amino acid change in the B chain makes the difference. , 1999, Journal of immunology.

[111]  J. Shimizu,et al.  Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance , 2002, Nature Immunology.

[112]  A. Imaoka,et al.  Proliferative recruitment of intestinal intraepithelial lymphocytes after microbial colonization of germ‐free mice , 1996, European journal of immunology.

[113]  A. Khoruts,et al.  Direct evidence that functionally impaired CD4+ T cells persist in vivo following induction of peripheral tolerance. , 1998, Journal of immunology.

[114]  R. Gershon,et al.  Infectious immunological tolerance. , 1971, Immunology.

[115]  A. Rudensky,et al.  Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo , 2002, Nature Immunology.

[116]  R M Zinkernagel,et al.  Localization dose and time of antigens determine immune reactivity. , 2000, Seminars in immunology.

[117]  D. Wraith,et al.  Role for IL-10 in Suppression Mediated by Peptide-Induced Regulatory T Cells In Vivo 1 , 2003, The Journal of Immunology.

[118]  P. Lowenstein,et al.  Active suppression of allogeneic proliferative responses by dendritic cells after induction of long-term allograft survival by CTLA4Ig. , 2003, Blood.

[119]  C. Boitard,et al.  Oral insulin administration and residual (β-cell function in recent-onset type 1 diabetes: a multicentre randomised controlled trial , 2000, The Lancet.

[120]  F. Lepault,et al.  Characterization of Peripheral Regulatory CD4+ T Cells That Prevent Diabetes Onset in Nonobese Diabetic Mice1 , 2000, The Journal of Immunology.

[121]  Ethan M. Shevach,et al.  CD4+CD25+ suppressor T cells: more questions than answers , 2002, Nature Reviews Immunology.

[122]  M. V. von Herrath,et al.  CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells. , 2002, Immunity.

[123]  B. Stockinger,et al.  Impairment of immunological memory in the absence of MHC despite survival of memory T cells , 2002, Nature Immunology.

[124]  U. Grohmann,et al.  CTLA-4–Ig regulates tryptophan catabolism in vivo , 2002, Nature Immunology.

[125]  M. Byrne,et al.  CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. , 2002, Immunity.