Abstract
Autoimmune gastritis (AIG) is an experimental model that closely resembles human autoimmune gastritis, the underlying pathology of pernicious anemia. Pathogenic CD4+ T cells are reactive to the parietal cell autoantigen, H/K ATPase, and are controlled by CD4+CD25+ T cells in an immunosuppressive cytokine-independent manner. Comparison of CD4+CD25+ T cell-mediated suppression in other autoimmune models shows inconsistencies with respect to requirements of cytokines for immunosuppression. More recent data, however, indicate that the evidence for requirement of IL-10 and TGF-ß could be due to the complex nature of the T cells causing the disease as well as the role of induced regulatory T cell populations. AIG provides a well-defined model that may allow for better analysis of CD4+CD25+ T cell in vivo biology. Evidence from this model indicates that immune responses must be initiated and then CD4+CD25+ T cells are recruited to control the quality of the immune response.
Access provided by Autonomous University of Puebla. Download to read the full chapter text
Chapter PDF
Similar content being viewed by others
Keywords
- Pernicious Anemia
- Autoimmune Gastritis
- Autoimmune Disease Model
- Suppressor Cell Population
- Tumor Necrosis Factor Receptor Ligand
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Alderuccio F, Gleeson PA, Berzins SP, Martin M, VanDriel IR, Toh BH (1997) Expression of the gastric H/K-ATPase alpha-subunit in the thymus may explain the dominant role of the beta-subunit in the pathogenesis of autoimmune gastritis. Autoimmunity 25:167–175
Alderuccio F, Cataldo V, van Driel IR, Gleeson PA, Toh BH (2000) Tolerance and autoimmunity to a gastritogenic peptide in TCR transgenic mice. Int Immunol 12:343–352
Alderuccio F, Sentry JW, Marshall AC J., Biondo M, Toh BH (2002) Animal models of human disease: Exp autoimmune gastritis-A model for autoimmune gastritis and pernicious anemia. Clinical Immunol 102:48–58
Annacker O, Pimenta-Araujo R, Burlen-Defranoux O, Barbosa TC, Cumano A, Bandeira A (2001) CD25(+) CD4(+) T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 166 3008–3018
Asano M, Toda M, Sakaguchi N, Sakaguchi S (1996) Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 184:387–396
Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F (1999) An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190:995–1003
Asseman C, Read S, Powrie F (2003) Colitogenic Th1 cells are present in the antigen-experienced T cell pool in normal mice: control by CD4+ regulatory T cells and IL-10. J Immunol 171:971–978
Bachmann MF, Kohler G, Ecabert B, Mak TW, Kopf M (1999) Cutting edge: Lympho-proliferative disease in the absence of CTLA-4 is not T cell autonomous. J Immunol 163 1128–1131
Barrett SP, Gleeson PA, deSilva H, Toh BH, vanDriel IR (1996) Interferon-gamma is required during the initiation of an organ-specific autoimmune disease. Eur J Immunol 26 1652–1655
Barthlott T, Kassiotis G, Stockinger B (2003) T cell regulation as a side effect of homeostasis and competition. J Exp Med 197:451–460
Bergman MP, Amedei A, D’Elios MM, Azzurri A, Benagiano M, Tamburini C, van der Zee R, Vandenbroucke-Grauls CM, Appelmelk BJ, Del Prete G (2003) Characterization of H+,K+-ATPase T cell epitopes in human autoimmune gastritis. Eur J Immunol 33:539–545
Biondo M, Nasa Z, Marshall A, Toh BH, Alderuccio F (2001) Local transgenic expression of granulocyte macrophage-colony stimulating factor initiates autoimmunity. J Immunol 166 2090–2099
Bruder D, Probst-Kepper M, Westendorf AM, Geffers R, Beissert S, Loser K, von Boehmer H, Buer J, Hansen W (2004) Neuropilin-1: a surface marker of regulatory T cells. Eur J Immunol 34:623–630
Cameron MJ, Arreaza GA, Zucker P, Chensue SW, Strieter RM, Chakrabarti S, Delovitch TL (1997) IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. J Immunol 159:4686–4692
Candon S, Mchugh RS, Foucras G, Natarajan K, Shevach EM, Margulies DH (2004) Spontaneous organ specific Th2-mediated autoimmunity in TCR transgenic mice. J Immunol 172:2917–2924
D’Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M, De Pont JJ, Cianchi F, Vandenbroucke-Grauls CM, Romagnani S, Appelmelk BJ, Del Prete G (2001) H+,K+-ATPase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis. Gastroenterology 120:377–386
De Jong YP, Rietdijk ST, Faubion WA, Abadia-Molina AC, Clarke K, Mizoguchi E, Tian J, Delaney T, Manning S, Gutierrez-Ramos J-C. et al (2004) Blocking inducible co-stimulator in the absence of CD28 impairs Th1 and CD25+ regulatory T cells in murine colitis. Int Immunol 16:205–213
De Silva HD, Gleeson PA, Toh BH, Van Driel IR, Carbone FR (1999) Identification of a gastritogenic epitope of the H/K ATPase beta-subunit. Immunology 96:145–151
Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G (2002) Human CD4+CD25+ regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells. J Exp Med 196:247–253
Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4(+)CD25(+) regulatory T cells. Nat Immunol 4:330–336
Foussat A, Cottrez F, Brun V, Fournier N, Breittmayer J-P, Groux H (2003) A comparative study between T regulatory type 1 and CD4+CD25+ T cells in the control of inflammation. J Immunol 171:5018–5026
Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A (2002) Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nature Immunol 3:33–41
Gottardi CJ, Caplan MJ (1993) Molecular requirements for the cell-surface expression of multisubunit ion-transport ATPase. Identification of protein domains that participate in Na, K-ATPase and H, K-ATPase subunit assembly. J Biol Chem 268:14342–14347
Homann D, Holz A, Bot A, Coon B, Wolfe T, Petersen J, Dyrberg TP, Grusby MJ, von Herrath MG (1999) Autoreactive CD4(+) T cells protect from autoimmune diabetes via bystander suppression using the IL-4/stat6 pathway. Immunity 11:463–472
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299:1057–1061
Jones CM, Callaghan JM, Gleeson PA, Mori Y, Masuda T, Toh BH (1991) The parietal-cell autoantibodies recognized in neonatal thymectomy-induced murine gastritis are the alpha-subunit and beta-subunit of the gastric proton pump. Gastroenterology 101:287–294
Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH (2002) Infectious tolerance: human CD25+ regulatory T cells convey suppressor activity to conventional CD4+ T helper cells. J Exp Med 196:255–260
Katakai T, Agata Y, Shimizu A, Ohshima C, Nishio A, Inaba M, Kasakura S, Mori KJ, Masuda T (1997) Structure of the TCR expressed on a gastritogenic T cell clone, II-6, frequent appearance of similar clonotypes in mice bearing autoimmune gastritis. Int Immunol 9:1849–1855
Katakai T, Hara T, Sugai M, Gonda H, Shimizu A (2003) Th1-biased tertiary lymphoid tissue supported by CXC chemokine ligand 13-producing stromal network in chronic lesions of autoimmune gastritis. J Immunol 171 4359–4368
Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4(+)CD25(+) T regulatory cells. Nature Immunol 4:337–342
Kim JD, Choi BK, Bae JS, Lee UH, Han IS, Lee HW, Youn BS, Vinay DS, Kwon B (2003) Cloning and characterization of GITR ligand. Genes Immun 4:564–569
Kohm AP, Williams JS, Miller SD (2004) Cutting edge: ligation of the glucocorticoid-induced TNF receptor enhances autoreactive CD4(+) T cell activation and experimental autoimmune encephalomyelitis. J Immunol 172:4686–4690
Kojima A, Prehn RT (1981) Genetic susceptibility to post-thymectomy autoimmune-diseases in mice. Immunogenetics 14:15–27
Krause I, Blank M, Shoenfeld Y (2000) Immunomodulation of experimental autoimmune diseases via oral tolerance. Crit Rev Immunol 20:1–16
Kukreja A, Cost G, Marker J, Zhang CH, Sun Z, Lin-Su K, Ten S, Sanz M, Exley M, Wilson B et al (2002) Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 109:131–140
Lafaille JJ, Nagashima K, Katsuki M, Tonegawa S (1994) High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient antimyelin basic-protein T-cell receptor transgenic mice. Cell 78:399–408
Laurie KL, Van Driel IR, Gleeson PA (2002) Role of CD4(+)CD25(+) immunoregulatory T cells in the induction of autoimmune gastritis. Immunol Cell Biol 80:567–573
Lehmann J, Huehn J, de la Rosa M, Maszyna F, Kretschmer U, Krenn V, Brunner M, Scheffold A, Hamann A (2002) Expression of the integrin alpha (E)beta (7) identities unique subsets of CD25(+) as well as CD25(−) regulatory T cells. Proc Natl Acad Sci U S America 99:13031–13036
Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS (2004) Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363:608–615
Liu H, Hu B, Xu D, Liew FY (2003) CD4+CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-β, CTLA-4. J Immunol 171:5012–5017
Marshall ACJ, Alderuccio F, Toh BH (2002) Fas/CD95 is required for gastric mucosal damage in autoimmune gastritis. Gastroenterology 123:780–789
Marshall ACJ, Toh BH, Alderuccio F (2004) Tumor necrosis factor alpha is not implicated in the genesis of experimental autoimmune gastritis. J Autoimmunity 22:1–11
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
Martinelli TM, vanDriel IR, Alderuccio F, Gleeson PA, Toh BH (1996) Analysis of mononuclear cell infiltrate and cytokine production in murine autoimmune gastritis. Gastroenterology 110:1791–1802
McHugh RS, Shevach EM (2002a) Cutting edge: depletion of CD4+CD25+ regulatory T cells is necessary, but not sufficient, for induction of organ-specific autoimmune disease. J Immunol 168:5979–5983
McHugh RS, Shevach EM (2002b) The role of suppressor T cells in regulation of immune responses. J Allergy Clin Immunol 110:693–702
McHugh R, Shevach E, Thornton A (2001a) Control of organ-specific autoimmunity by immunoregulatory CD4+CD25+ T cells. Microb Infect 3:919–927
McHugh RS, Shevach EM, Margulies DH, Natarajan K (2001b) A T cell receptor transgenic model of severe, spontaneous organ-specific autoimmunity. Eur J Immunol 31:2094–2103
McHugh RS, Whitters MJ, Piccirillo CA, Young DA, Shevach EM, Collins M, Byrne MC (2002) CD4+CD25+ Immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 16:311–323
Min B, McHugh R, Sempowski GD, Mackall C, Foucras G, Paul WE (2004) Neonates support lymphopenia-induced proliferation. Immunity 18:131–140
Mottet C, Uhlig HH, Powrie F (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170 3939–3943
Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629–644
Nishio A, Katakai T, Oshima C, Kasakura S, Sakai M, Yonehara S, Suda T, Nagata S, Masuda T (1996) A possible involvement of Fas-Fas ligand signaling in the pathogenesis of murine autoimmune gastritis. Gastroenterology 111:959–967
Oldenhove G, de Heusch M, Urbain-Vansanten G, Urbain J, Maliszewski C, Leo O, Moser M (2003) CD4(+) CD25(+) regulatory T cells control T helper cell type 1 responses to foreign antigens induced by mature dendritic cells in vivo. J Exp Med 198:259–266
Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128–3133
Piccirillo CA, Shevach EM (2004) Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 16:81–88
Piccirillo CA, Letterio JJ, Thornton AM, Mchugh RS, Mamura M, Mizuhara H, Shevach EM (2002) CD4+CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor beta1 production and responsiveness. J Exp Med 196:237–246
Powrie F, Leach M, Coffman RL (1994) CD45Rbhigh Cd4+ T-cells induce a pathogenic Th1 response in the colon when transferred to C-B-17 Scid mice which is prevented by co-transfer of the Cd45rblow population. J Cell Biochem 418–425
Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL (1996) A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4(+) T cells. J Exp Med 183:2669–2674
Read S, Malmstrom V, Powrie F (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302
Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Ann Rev Immunol 22:531–562
Sakaguchi S, Ermak TH, Toda M, Berg LJ, Ho W, Destgroth BF, Peterson PA, Sakaguchi N, Davis MM (1994) Induction of autoimmune-disease in mice by germline alteration of the T-cell receptor gene-expression. J Immunol 152:1471–1484
Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunological self-tolerance maintained by activated T-cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164
Salama AD, Chaudhry AN, Holthaus KA, Mosley K, Kalluri R, Sayegh MH, Lechler RI, Pusey CD, Lightstone L (2003) Regulation by CD25(+) lymphocytes of autoantigen-specific T-cell responses in Goodpasture’s (anti-GBM) disease. Kidney Int 64:1685–1694
Salomon B, Lenschow DJ, Rhee L, Ashourian N, Singh B, Sharpe A, Bluestone JA (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4(+)CD25(+) immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440
Scarff KJ, Pettitt JM, VanDriel IR, Gleeson PA, Toh BH (1997) Immunization with gastric H+/K+-ATPase induces a reversible autoimmune gastritis. Immunol 92:91–98
Scheinecker C, McHugh R, Shevach EM, Germain RN (2002) Constitutive presentation of a natural tissue autoantigen exclusively by dendritic cells in the draining lymph node. J Exp Med 196:1079–1090
Seddon B, Mason D (1999) Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor beta and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4(+)CD45RC(−) cells and CD4(+)CD8(−) thymocytes. J Exp Med 189:279–288
Shevach EM (2000) Regulatory T cells in autoimmmunity. Ann Rev Immunol 18:423–449
Shevach EM (2001) Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 193:F41–F45
Shevach EM (2002) CD4+CD25+ suppressor T cells:more questions than answers. Nat Rev Immunol 2:389–400
Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25(+)CD4(+) T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211–5218
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142
Stassen M, Fondel S, Bopp R, Richter C, Muller C, Kubach J, Becker C, Knop J, Enk AH, Schmitt S et al (2004) Human CD25+ regulatory T cells: two subsets defined by the integrins α4β7 or β4β1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol 34:1303–1311
Steinman RM, Turley S, Mellman I, Inaba K (2000) The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med 191:411–416
Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Ann Rev Immunol 21:685–711
Stephens GL, McHugh RS, Whitters MJ, Young DA, Collins M, Shevach EM (2004) Engagement of GITR on effector T cells by its ligand mediates resistance to suppression by CD4+CD25+ T cells. J Immunol 173:5008–5020
Suri-Payer E, Cantor H (2001) Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4(+)CD25(+) T cells. J Autoimmunity 16:115–123
Suri-Payer E, Amar AZ, Thornton AM, Shevach EM (1998) CD4(+)CD25(+) T cells inhibit both the induction and effector function of autoreactive T cells and represent a unique lineage of immunoregulatory cells. J Immunol 160:1212–1218
Suri-Payer E, Amar AZ, McHugh R, Natarajan K, Margulies DH, Shevach EM (1999) Post-thymectomy autoimmune gastritis: fine specificity and pathogenicity of anti-H/K ATPase-reactive T cells. Eur J Immunol 29:669–677
Sutmuller RPM, van Duivenvoorde LM, van Elsas A, Schumacher TNM, Wildenberg ME, Allison JP, Toes REM, Offringa R, Melief CJM (2001) Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25+ regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med 194:823–832
Szanya V, Ermann J, Taylor C, Holness C, Fathman CG (2002) The Subpopulation of CD4(+) CD25(+) splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol 169:2461–2465
Taguchi O, Takahashi T (1996) Administration of anti-interleukin-2 receptor alpha antibody in vivo induces localized autoimmune disease. Eur J Immunol 26:1608–1612
Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S (1998) Immunologic self-tolerance maintained by CD25(+)CD4(+) naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969–1980
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 192:303–309
Thornton AM, Shevach EM (1998) CD4(+)CD25(+) immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188:287–296
Thornton AM, Shevach EM (2000) Suppressor effector function of CD4(+)CD25(+) immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190
Thornton A, Piccirillo CA, Shevach EM (2004a) Activation requirements for the induction of CD4+CD25+ T cells suppressor function. Eur J Immunol 34:366–376
Thornton AM, Donovan EE, Piccirillo CA, Shevach EM (2004b) Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function. J Immunol 172:6519–6523
Toh BH, vanDriel IR, Gleeson PA (1997) Mechanisms of disease: pernicious anemia. New Engl J Med 337:1441–1448
Toh BH, Sentry JW, Alderuccio F (2000) The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis. Immunol Today 21:348–354
Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, Waldmann H (2003) Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells. Proc Natl Acad Sci U S A 100:15059–15064
Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4(+)CD25(+) regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979
Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, Thompson CB, Bluestone JA (1994) CTLA-4 can function as a negative regulator of T-cell activation. Immunity 1:405–413
Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988
Zelenika D, Adams E, Humm S, Graca L, Thompson S, Cobbold SP, Waldmann H (2002) Regulatory T cells overexpress a subset of Th2 gene transcripts. J Immunol 168:1069–1079
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
McHugh, R.S. (2005). Autoimmune Gastritis Is a Well-Defined Autoimmune Disease Model for the Study of CD4+CD25+ T Cell-Mediated Suppression. In: Compans, R., et al. CD4+CD25+ Regulatory T Cells: Origin, Function and Therapeutic Potential. Current Topics in Microbiology and Immunology, vol 293. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27702-1_8
Download citation
DOI: https://doi.org/10.1007/3-540-27702-1_8
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-24444-8
Online ISBN: 978-3-540-27702-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)