The Essential Role of Circulating Thyroglobulin in Maintaining Dominance of Natural Regulatory T Cell Function to Prevent Autoimmune Thyroiditis

Abstract

Several key findings from the late 1960s to mid-1970s regarding thyroid hormone metabolism and circulating thyroglobulin composition converged with studies pertaining to the role of T lymphocytes in autoimmune thyroiditis. These studies cemented the foundation for subsequent investigations into the existence and antigenic specificity of thymus-derived natural regulatory T cells (nTregs). These nTregs prevented the development of autoimmune thyroiditis, despite the ever-present genetic predisposition, autoantigen (thyroglobulin), and thyroglobulin-reactive T cells. Guided by the hypothalamus-pituitary-thyroid axis as a fixed set-point regulator in thyroid hormone metabolism, we used a murine model and compared at key junctures the capacity of circulating thyroglobulin level (raised by thyroid-stimulating hormone or exogenous thyroglobulin administration) to strengthen self-tolerance and resist autoimmune thyroiditis. The findings clearly demonstrated an essential role for raised circulating thyroglobulin levels in maintaining the dominance of nTreg function and inhibiting thyroid autoimmunity. Subsequent identification of thyroglobulin-specific nTregs as CD4⁺CD25⁺Foxp3⁺ in the early 2000s enabled the examination of probable mechanisms of nTreg function. We observed that whenever nTreg function was perturbed by immunotherapeutic measures, opportunistic autoimmune disorders invariably surfaced. This review highlights the step-wise progression of applying insights from endocrinologic and immunologic studies to advance our understanding of the clonal balance between natural regulatory and autoreactive T cells. Moreover, we focus on how tilting the balance in favor of maintaining peripheral tolerance could be achieved. Thus, murine autoimmune thyroiditis has served as a unique model capable of closely simulating natural physiologic conditions.

Key words

natural regulatory T cells - experimental autoimmune thyroiditis - autoreactive T cells - circulating thyroglobulin - thyroid-stimulating hormone - thyrotropin-releasing hormone

Publication History

Received: 04 February 2015

Accepted: 12 March 2015

Article published online:
09 July 2015

• References

• 1 Vladutiu AO, Rose NR. Autoimmune murine thyroiditis: relation to histocompatibility (H-2) type. Science 1971; 174: 1137-1139
• 2 Vladutiu AO, Rose NR. Cellular basis of the genetic control of immune responsiveness to murine thyroglobulin in mice. Cell Immunol 1975; 17: 106-113
• 3 Daniel PM, Pratt OE, Roitt IM, Torrigiani G. The release of thyroglobulin from the thyroid gland into thyroid lymphatics; the identification of thyroglobulin in the thyroid lymph and in the blood of monkeys by physical and immunological methods and its estimation by radioimmunoassay. Immunology 1967; 12: 489-504
• 4 Uller RP, Van Herle AJ, Chopra IJ. Comparison of alterations in circulating thyroglobulin, triiodothyronine and thyroxine in response to exogenous (bovine) and endogenous (human) thyrotropin. J Clin Endocrinol Metab 1973; 37: 741-745
• 5 Kojima A, Tanaka-Kojima Y, Sakakura T, Nishizuka Y. Spontaneous development of autoimmune thyroiditis in neonatally thymectomized mice. Lab Invest 1976; 34: 550-557
• 6 Penhale WJ, Farmer A, Irvine WJ. Thyroiditis in T cell-depleted rats: influence of strain, radiation dose, adjuvants and antilymphocyte serum. Clin Exp Immunol 1975; 21: 362-375
• 7 Segerson TP, Kauer J, Wolfe HC, Mobtaker H, Wu P, Jackson IM, Lechan RM. Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus. Science 1987; 238: 78-80
• 8 Fliers E, Kalsbeek A, Boelen A. Beyond the fixed setpoint of the hypothalamus-pituitary-thyroid axis. Eur J Endocrinol 2014; 171: R197-R208
• 9 Belyavin G, Trotter WR. Investigations of thyroid antigens reacting with Hashimoto sera; evidence for an antigen other than thyroglobulin. Lancet 1959; I: 648-652
• 10 Yoshida H, Amino N, Yagawa K, Uemura K, Satoh M, Miyai K, Kumahara Y. Association of serum antithyroid antibodies with lymphocytic infiltration of the thyroid gland: studies of seventy autopsied cases. J Clin Endocrinol Metab 1978; 46: 859-862
• 11 McLachlan SM, Rapoport B. Thyroid peroxidase as an autoantigen. Thyroid 2007; 17: 939-948
• 12 Kong YM, Morris GP, Brown NK, Yan Y, Flynn JC, David CS. Autoimmune thyroiditis: a model uniquely suited to probe regulatory T cell function. J Autoimmun 2009; 33: 239-246
• 13 Kong YM, Brown NK, Flynn JC, McCormick DJ, Brusic V, Morris GP, David CS. Efficacy of HLA-DRB1 *03:01 and H2E transgenic mouse strains to correlate pathogenic thyroglobulin epitopes for autoimmune thyroiditis. J Autoimmun 2011; 37: 63-70
• 14 Esquivel PS, Rose NR, Kong YM. Induction of autoimmunity in good and poor responder mice with mouse thyroglobulin and lipopolysaccharide. J Exp Med 1977; 145: 1250-1263
• 15 ElRehewy M, Kong YM, Giraldo AA, Rose NR. Syngeneic thyroglobulin is immunogenic in good responder mice. Eur J Immunol 1981; 11: 146-151
• 16 Okayasu I, Kong YM, David CS, Rose NR. In vitro T-lymphocyte proliferative response to mouse thyroglobulin in experimental autoimmune thyroiditis. Cell Immunol 1981; 61: 32-39
• 17 Kong YM, Okayasu I, Giraldo AA, Beisel KW, Sundick RS, Rose NR, David CS, Audibert F, Chedid L. Tolerance to thyroglobulin by activating suppressor mechanisms. Ann N Y Acad Sci 1982; 392: 191-209
• 18 Rose NR, Kong YM, Okayasu I, Giraldo AA, Beisel K, Sundick RS. T-cell regulation in autoimmune thyroiditis. Immunol Rev 1981; 55: 299-314
• 19 Kong YM, Wiger DL. Interrelationships of tolerance and immunity. I. Induction of immunologic tolerance in adult mice to bovine γ globulin purified in vivo. J Immunol 1970; 105: 370-378
• 20 Kong YM, David CS, Giraldo AA, ElRehewy M, Rose NR. Regulation of autoimmune response to mouse thyroglobulin: influence of H-2D-end genes. J Immunol 1979; 123: 15-18
• 21 Ikekubo K, Kishihara M, Sanders J, Jutton J, Schneider AB. Differences between circulating and tissue thyroglobulin in rats. Endocrinology 1981; 109: 427-432
• 22 Okayasu I, Kong YM, Rose NR, David CS. Induction of tolerance in experimental autoimmune thyroiditis with soluble mouse thyroglobulin. Fed Amer Soc Exp Biol Proc 1980; 39: 667 (Abstract)
• 23 Lewis M, Giraldo AA, Kong YM. Resistance to experimental autoimmune thyroiditis induced by physiologic manipulation of thyroglobulin level. Clin Immunol Immunopathol 1987; 45: 92-104
• 24 Gibaldi M, Perrier D. Drugs and the pharmaceutical sciences: Pharmacokinetics. New York: Dekker, 1975; 1–329
• 25 Vanderpump MPJ, Tunbridge WMG, French JM, Appleton D, Bates D, Clark F, Grimley Evans J, Hasan DM, Rodgers H, Tunbridge F, Young ET. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham survey. Clin Endocrinol 1995; 43: 55-68
• 26 Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002; 87: 489-499
• 27 Creemers P, Giraldo AA, Rose NR, Kong YM. T-cell subsets in the thyroids of mice developing autoimmune thyroiditis. Cell Immunol 1984; 87: 692-697
• 28 Creemers P, Rose NR, Kong YM. Experimental autoimmune thyroiditis: in vitro cytotoxic effects of T lymphocytes on thyroid monolayers. J Exp Med 1983; 157: 559-571
• 29 Sakaguchi S, Takahashi T, Nishizuka Y. Study on cellular events in post-thymectomy autoimmune oophoritis in mice. II. Requirement of Lyt-1 cells in normal female mice for the prevention of oophoritis. J Exp Med 1982; 156: 1577-1586
• 30 Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J Exp Med 1985; 161: 72-87
• 31 Cobbold SP, Jayasuriya A, Nash A, Prospero TD, Waldmann H. Therapy with monoclonal antibodies by elimination of T-cell subsets in vivo. Nature 1984; 312: 548-551
• 32 Cobbold SP, Martin G, Qin S, Waldmann H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature 1986; 323: 164-166
• 33 Waldmann H. Tolerance can be infectious. Nat Immunol 2008; 9: 1001-1003
• 34 Waldmann H, Cobbold S. Regulatory T cells: context matters. Immunity 2009; 30: 613-615
• 35 Kong YM, Wei W-Z, Tomer Y. Opportunistic autoimmune disorders: from immunotherapy to immune dysregulation. Ann N Y Acad Sci 2010; 1183: 222-236
• 36 Kong YM, Flynn JC. Opportunistic autoimmune disorders potentiated by immune-checkpoint inhibitors anti-CTLA-4 and anti-PD-1. Front Immunol 2014; 5: 206
• 37 Lorenzi AR, Clarke AM, Wooldridge T, Waldmann H, Hale G, Symmons D, Hazleman BL, Isaacs JD. Morbidity and mortality in rheumatoid arthritis patients with prolonged therapy-induced lymphopenia: twelve-year outcomes. Arthritis Rheum 2008; 58: 370-375
• 38 Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786-1801
• 39 Kong YM, Giraldo AA, Waldmann H, Cobbold SP, Fuller BE. Resistance to experimental autoimmune thyroiditis: L3T4⁺ cells as mediators of both thyroglobulin-activated and TSH-induced suppression. Clin Immunol Immunopathol 1989; 51: 38-54
• 40 Fuller BE, Okayasu I, Simon LL, Giraldo AA, Kong YM. Characterization of resistance to murine experimental autoimmune thyroiditis: duration and afferent action of thyroglobulin- and TSH-induced suppression. Clin Immunol Immunopathol 1993; 69: 60-68
• 41 Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155: 1151-1164
• 42 Lowenthal JW, Corthésy P, Tougne C, Lees R, MacDonald HR, Nabholz M. High and low affinity IL 2 receptors: analysis by IL 2 dissociation rate and reactivity with monoclonal anti-receptor antibody PC61. J Immunol 1985; 135: 3988-3994
• 43 Morris GP, Chen L, Kong YM. CD137 signaling interferes with activation and function of CD4⁺CD25⁺ regulatory T cells in induced tolerance to experimental autoimmune thyroiditis. Cell Immunol 2003; 226: 20-29
• 44 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057-1061
• 45 Khattri R, Cox T, Yasayko S, Ramsdell F. An essential role for Scurfin in CD4⁺CD25⁺ T regulatory cells. Nat Immunol 2003; 4: 337-342
• 46 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4⁺CD25⁺ regulatory T cells. Nat Immunol 2003; 4: 330-336
• 47 Morris GP, Brown NK, Kong YM. Naturally-existing CD4⁺CD25⁺Foxp3⁺ regulatory T cells are required for tolerance to experimental autoimmune thyroiditis induced by either exogenous or endogenous autoantigen. J Autoimmun 2009; 33: 68-76
• 48 Verginis P, Li HS, Carayanniotis G. Tolerogenic semimature dendritic cells suppress experimental autoimmune thyroiditis by activation of thyroglobulin-specific CD4⁺CD25⁺ T cells. J Immunol 2005; 174: 7433-7439
• 49 Venuprasad K, Kong YM, Farrar MA. Control of Th2-mediated inflammation by regulatory T cells. Am J Pathol 2010; 177: 525-531
• 50 Beisel KW, David CS, Giraldo AA, Kong YM, Rose NR. Regulation of experimental autoimmune thyroiditis: mapping of susceptibility to the I-A subregion of the mouse H-2. Immunogenetics 1982; 15: 427-431
• 51 Kong YM, David CS, Lomo LC, Fuller BE, Motte RW, Giraldo AA. Role of mouse and human class II transgenes in susceptibility to and protection against mouse autoimmune thyroiditis. Immunogenetics 1997; 46: 312-317
• 52 Morris GP, Yan Y, David CS, Kong YM. H2A- and H2E-derived CD4⁺CD25⁺ regulatory T cells: a potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis. J Immunol 2005; 174: 3111-3116
• 53 Wan Q, Shah R, McCormick DJ, Lomo LC, Giraldo AA, David CS, Kong YM. H2-E transgenic class II-negative mice can distinguish self from nonself in susceptibility to heterologous thyroglobulins in autoimmune thyroiditis. Immunogenetics 1999; 50: 22-30
• 54 Brown NK, McCormick DJ, Brusic V, David CS, Kong YM. A novel H2A^-E⁺ transgenic model susceptible to human but not mouse thyroglobulin-induced autoimmune thyroiditis: Identification of mouse pathogenic epitopes. Cell Immunol 2008; 251: 1-7
• 55 Ban Y, Greenberg DA, Concepcion E, Skrabanek L, Villanueva R, Tomer Y. Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci U S A 2003; 100: 15119-15124
• 56 Menconi F, Monti MC, Greenberg DA, Oashi T, Osman R, Davies TF, Ban Y, Jacobson EM, Concepcion ES, Li CW, Tomer Y. Molecular amino acid signatures in the MHC class II peptide-binding pocket predispose to autoimmune thyroiditis in humans and in mice. Proc Natl Acad Sci U S A 2008; 105: 14034-14039
• 57 Kong YM, Lomo LC, Motte RW, Giraldo AA, Baisch J, Strauss G, Hämmerling GJ, David CS. HLA-DRB1 polymorphism determines susceptibility to autoimmune thyroiditis in transgenic mice: definitive association with HLA-DRB1*0301 (DR3) gene. J Exp Med 1996; 184: 1167-1172
• 58 Muixi L, Carrascal M, Alvarez I, Daura X, Marti M, Armengol M, Pinilla C, Abian J, Pujol-Borrell R, Jaraquemada D. Thyroglobulin peptides associate in vivo to HLA-DR in autoimmune thyroid glands. J Immunol 2008; 181: 795-807
• 59 Morris GP, Kong YM. Tolerance to autoimmune thyroiditis: CD4⁺CD25⁺ regulatory T cells influence susceptibility but do not supersede MHC class II restriction. Front Biosci 2006; 11: 1234-1243
• 60 Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223-243
• 61 Nabozny GH, Kong YM. Circumvention of the induction of resistance in murine experimental autoimmune thyroiditis by recombinant IL-1β. J Immunol 1992; 149: 1086-1092
• 62 Zhang W, Flynn JC, Kong YM. IL-12 prevents tolerance induction with mouse thyroglobulin by priming pathogenic T cells in experimental autoimmune thyroiditis: role of IFN-γ and the costimulatory molecules CD40L and CD28. Cell Immunol 2001; 208: 52-61
• 63 Zhang W, Kong YM. Noninvolvement of IL-4 and IL-10 in tolerance induction to experimental autoimmune thyroiditis. Cell Immunol 1998; 187: 95-102
• 64 Morris GP, Kong YM. Interference with CD4⁺CD25⁺ T-cell-mediated tolerance to experimental autoimmune thyroiditis by glucocorticoid-induced tumor necrosis factor receptor monoclonal antibody. J Autoimmun 2006; 26: 24-31
• 65 Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 1995; 182: 459-465
• 66 Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S. CTLA-4 control over Foxp3⁺ regulatory T cell function. Science 2008; 322: 271-275
• 67 Tai X, Van Laethem F, Pobezinsky L, Guinter T, Sharrow SO, Adams A, Granger L, Kruhlak M, Lindsten T, Thompson CB, Feigenbaum L, Singer A. Basis of CTLA-4 function in regulatory and conventional CD4⁺ T cells. Blood 2012; 119: 5155-5163
• 68 Wakamatsu E, Mathis D, Benoist C. Convergent and divergent effects of costimulatory molecules in conventional and regulatory CD4⁺ T cells. Proc Natl Acad Sci USA 2013; 110: 1023-1028
• 69 Ueda H, Howson JMM, Esposito L, Heward J, Snook H, Chamberlain G, Rainbow DB, Hunter KMD, Smith AN, Di Genova G, Herr MH, Dahlman I, Payne F, Smyth D, Lowe C, Twells RCJ, Howlett S, Healy B, Nutland S, Rance HE, Everett V, Smink LJ, Lam AC, Cordell HJ, Walker NM, Bordin C, Hulme J, Motzo C, Cucca F, Hess JF, Metzker ML, Rogers J, Gregory S, Allahabadia A, Nithiyananthan R, Toumilehto-Wolf E, Tuomilehto J, Bingley P, Gillespie KM, Undlien DE, Rønningen KS, Guja C, Ionescu-Tírgoviste C, Savage DA, Maxwell AP, Carson DJ, Patterson CC, Franklyn JA, Clayton DG, Peterson LB, Wicker LS, Todd JA, Gough SCL. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 2003; 423: 506-511
• 70 Ban Y, Davies TF, Greenberg DA, Kissin A, Marder B, Murphy B, Concepcion ES, Villanueva RB, Barbesino G, Ling V, Tomer Y. Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease. Genes Immun 2003; 4: 586-593
• 71 Corsello SM, Barnabei A, Marchetti P, De VL, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab 2013; 98: 1361-1375
• 72 Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, O’Day SJ, Hoos A, Humphrey R, Berman DM, Lonberg N, Korman AJ. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 2013; 1291: 1-13
• 73 Caturegli P, Lupi I, Landek-Salgado M, Kimura H, Rose NR. Pituitary autoimmunity: 30 years later. Autoimmun Rev 2008; 7: 631-637
• 74 Torino F, Barnabei A, De VL, Salvatori R, Corsello SM. Hypophysitis induced by monoclonal antibodies to cytotoxic T lymphocyte antigen 4: challenges from a new cause of a rare disease. Oncologist 2012; 17: 525-535
• 75 Iwama S, De Remigis A, Callahan MK, Slovin SF, Wolchok JD, Caturegli P. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 2014; 6: 230ra45
• 76 Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012; 30: 2691-2697
• 77 Wei W-Z, Jacob JB, Zielinski JF, Flynn JC, Shim KD, Alsharabi G, Giraldo AA, Kong YM. Concurrent induction of antitumor immunity and autoimmune thyroiditis in CD4⁺CD25⁺ regulatory T cell-depleted mice. Cancer Res 2005; 65: 8471-8478
• 78 Jacob JB, Kong YM, Meroueh C, Snower DP, David CS, Ho Y-S, Wei W-Z. Control of Her-2 tumor immunity and thyroid autoimmunity by MHC and regulatory T cells. Cancer Res 2007; 67: 7020-7027
• 79 Jacob JB, Kong YM, Nalbantoglu I, Snower DP, Wei W-Z. Tumor regression following DNA vaccination and regulatory T cell depletion in neu transgenic mice leads to an increased risk for autoimmunity. J Immunol 2009; 182: 5873-5881
• 80 Kari S, Flynn JC, Zulfiqar M, Snower DP, Elliott BE, Kong YM. Enhanced autoimmunity associated with induction of tumor immunity in thyroiditis-susceptible mice. Thyroid 2013; 23: 1590-1599
• 81 Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, Riess D, Hein MY, Buch T, Polic B, Schonle A, Zeiser R, Schmitt-Graff A, Kretschmer K, Klein L, Korn T, Sakaguchi S, Schmidt-Supprian M. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 2014; 41: 722-736