Skip to main content

Advertisement

SpringerLink
Log in

Role of TGF-β in Self-Peptide Regulation of Autoimmunity

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Transforming growth factor (TGF)-β has been implicated in regulation of the immune system, including autoimmunity. We have found that TGF-β is readily produced by T cells following immunization with self-peptide epitopes that downregulate autoimmune responses in type 1 diabetes (T1D) prone nonobese diabetic (NOD) mice. These include multiple peptide epitopes derived from the islet β-cell antigens GAD65 (GAD65 p202-221, GAD65 p217-236), GAD67 (GAD67 p210-229, GAD67 p225-244), IGRP (IGRP p123-145, IGRP p195-214) and insulin B-chain (Ins. B:9-23) that protected NOD mice from T1D. Immunization of NOD mice with the self-MHC class II I-Ag7 β-chain-derived peptide, I-Aβg7 p54-76 also induced large amounts of TGF-β and also protected these mice from diabetes development. These results indicate that peptides derived from disease related self-antigens and MHC class II molecules primarily induce TGF-β producing regulatory Th3 and Tr1-like cells. TGF-β produced by these cells could enhance the differentiation of induced regulatory iTreg and iTreg17 cells to prevent induction and progression of autoimmune diseases. We therefore suggest that peripheral immune tolerance could be induced and maintained by immunization with self-peptides that induce TGF-β producing T cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Bach JF (1994) Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev 15:516–542

    Article  CAS  PubMed  Google Scholar 

  • Bach JF, Chatenoud L (2001) Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol 19:131–161

    Article  CAS  PubMed  Google Scholar 

  • Battaglia M, Gregori S, Bacchetta R et al (2006a) Tr1 cells: from discovery to their clinical application. Semin Immunol 18:120–127

    Article  CAS  PubMed  Google Scholar 

  • Battaglia M, Stabilini A, Draghici E et al (2006b) Induction of tolerance in type 1 diabetes via both CD4+CD25+T regulatory cells and T regulatory type 1 cells. Diabetes 55:1571–1580

    Article  CAS  PubMed  Google Scholar 

  • Bellemore SM, Nikoopour E, Schwartz JA et al (2015) Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice. Clin Exp Immunol 182:261–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bluestone JA, Tang Q, Sedwick CE (2008) T regulatory cells in autoimmune diabetes: past challenges, future prospects. J Clin Immunol 28:677–684

    Article  CAS  PubMed  Google Scholar 

  • Chaturvedi P, Qin HY, Chou H et al (1997) Modulation of insulin-dependent diabetes mellitus (IDDM) in NOD mice by autoreactive T cells. Crit Rev Immunol 17:519–528

    CAS  PubMed  Google Scholar 

  • Chaturvedi P, Agrawal B, Zechel M et al (2000) A self MHC class II beta-chain peptide prevents diabetes in nonobese diabetic mice. J Immunol 164:6610–6620

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Kuchroo VK, Inobe J et al (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237–1240

    Article  CAS  PubMed  Google Scholar 

  • Chen C, Lee WH, Yun P et al (2003) Induction of autoantigen-specific Th2 and Tr1 regulatory T cells and modulation of autoimmune diabetes. J Immunol 171:733–744

    Article  CAS  PubMed  Google Scholar 

  • Clemente-Casares X, Blanco J, Ambalavanan P et al (2016) Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530:434–440

    Article  CAS  PubMed  Google Scholar 

  • Cottrez F, Hurst SD, Coffman RL et al (2000) T regulatory cells 1 inhibit a Th2-specific response in vivo. J Immunol 165:4848–4853

    Article  CAS  PubMed  Google Scholar 

  • Daniel D, Wegmann DR (1996) Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23). Proc Natl Acad Sci USA 93:956–960

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delong T, Baker RL, He J et al (2013) Novel autoantigens for diabetogenic CD4 T cells in autoimmune diabetes. Immunol Res 55:167–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Delovitch TL, Singh B (1997) The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7:727–738

    Article  CAS  PubMed  Google Scholar 

  • Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584

    Article  CAS  PubMed  Google Scholar 

  • Di Lorenzo TP, Peakman M, Roep BO (2007) Translational mini-review series on type 1 diabetes: systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 148:1–16

    Article  PubMed  PubMed Central  Google Scholar 

  • Elliott JF, Qin HY, Bhatti S et al (1994) Immunization with the larger isoform of mouse glutamic acid decarboxylase (GAD67) prevents autoimmune diabetes in NOD mice. Diabetes 43:1494–1499

    Article  CAS  PubMed  Google Scholar 

  • Gomez-Tourino I, Arif S, Eichmann M et al (2016) T cells in type 1 diabetes: instructors, regulators and effectors: a comprehensive review. J Autoimmun 66:7–16

    Article  CAS  PubMed  Google Scholar 

  • Groux H (2003) Type 1 T-regulatory cells: their role in the control of immune responses. Transplantation 75(9 Suppl):8S–12S

    Article  CAS  PubMed  Google Scholar 

  • Groux H, O’Garra A, Bigler M et al (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737–742

    Article  CAS  PubMed  Google Scholar 

  • Han HS, Jun HS, Utsugi T et al (1996) A new type of CD4+ suppressor T cell completely prevents spontaneous autoimmune diabetes and recurrent diabetes in syngeneic islet-transplanted NOD mice. J Autoimmun 9:331–339

    Article  CAS  PubMed  Google Scholar 

  • Han HS, Jun HS, Utsugi T et al (1997) Molecular role of TGF-beta, secreted from a new type of CD4+ suppressor T cell, NY4.2, in the prevention of autoimmune IDDM in NOD mice. J Autoimmun 10:299–307

    Article  CAS  PubMed  Google Scholar 

  • Han B, Serra P, Amrani A et al (2005a) Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med 11:645–652

    Article  CAS  PubMed  Google Scholar 

  • Han B, Serra P, Yamanouchi J et al (2005b) Developmental control of CD8 T cell-avidity maturation in autoimmune diabetes. J Clin Invest 115:1879–1887

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishigame H, Zenewicz LA, Sanjabi S et al (2013) Excessive Th1 responses due to the absence of TGF-β signaling cause autoimmune diabetes and dysregulated Treg cell homeostasis. Proc Natl Acad Sci USA 110:6961–6966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jun HS, Khil LY, Yoon JW (2002) Role of glutamic acid decarboxylase in the pathogenesis of type 1 diabetes. Cell Mol Life Sci 59:1892–1901

    Article  CAS  PubMed  Google Scholar 

  • Kaufman DL, Clare-Salzler M, Tian J et al (1993) Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes. Nature 366:69–72

    Article  CAS  PubMed  Google Scholar 

  • Kaufman DL, Tisch R, Sarvetnick N et al (2001) Report from the 1st international NOD mouse T-Cell workshop and the follow-up mini-workshop. Diabetes 50:2459–2463

    Article  CAS  PubMed  Google Scholar 

  • Kim SK, Tarbell KV, Sanna M et al (2004) Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206–220-specific T cells. Proc Natl Acad Sci USA 101:14204–14209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim D, Lee SM, Jun HS (2017) Impact of T-cell-specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice. Immunol Cell Biol 95:287–296

    Article  CAS  PubMed  Google Scholar 

  • King C, Davies J, Mueller R et al (1998) TGF-beta1 alters APC preference, polarizing islet antigen responses toward a Th2 phenotype. Immunity 8:601–613

    Article  CAS  PubMed  Google Scholar 

  • Kitani A, Chua K, Nakamura K et al (2000) Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J Immunol 165:691–702

    Article  CAS  PubMed  Google Scholar 

  • Ko HJ, Chee J, Sutherland RM et al (2014) Functional cytotoxic T lymphocytes against IGRP206-214 predict diabetes in the non-obese diabetic mouse. Immunol Cell Biol 92:640–644

    Article  CAS  PubMed  Google Scholar 

  • Koevary SB (1991) Effects of incubation of islet cells with transforming growth factor beta (TGF-beta) on their susceptibility to diabetic lymphocyte mediated destruction in the rat, in vitro. Diabetes Res 18:123–127

    CAS  PubMed  Google Scholar 

  • Lernmark A, Larsson HE (2013) Immune therapy in type 1 diabetes mellitus. Nat Rev Endocrinol 9:92–103

    Article  CAS  PubMed  Google Scholar 

  • Letterio JJ, Roberts AB (1998) Regulation of immune responses by TGF-beta. Annu Rev Immunol 16:137–161

    Article  CAS  PubMed  Google Scholar 

  • Li MO, Wan YY, Sanjabi S et al (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146

    Article  CAS  PubMed  Google Scholar 

  • Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26:579–591

    Article  CAS  PubMed  Google Scholar 

  • Lieberman SM, Evans AM, Han B et al (2003) Identification of the beta cell antigen targeted by a prevalent population of pathogenic CD8+ T cells in autoimmune diabetes. Proc Natl Acad Sci USA 100:8384–8388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mallone R, Brezar V, Boitard C (2011) T cell recognition of autoantigens in human type 1 diabetes: clinical perspectives. Clin Dev Immunol 2011:513210

    Article  PubMed  PubMed Central  Google Scholar 

  • Maron R, Melican NS, Weiner HL (1999) Regulatory Th2-type T cell lines against insulin and GAD peptides derived from orally- and nasally-treated NOD mice suppress diabetes. J Autoimmun 12:251–258

    Article  CAS  PubMed  Google Scholar 

  • Martin CC, Bischof LJ, Bergman B et al (2001) Cloning and characterization of the human and rat islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) genes. J Biol Chem 276:25197–25207

    Article  CAS  PubMed  Google Scholar 

  • McCarron MJ, Marie JC (2014) TGF-β prevents T follicular helper cell accumulation and B cell autoreactivity. J Clin Invest 124:4375–4386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mukherjee R, Chaturvedi P, Agrawal B et al (2003a) Regulation of type 1 diabetes by a self-MHC class II peptide: role of transforming growth factor beta (TGF-beta). Cell Mol Biol 49:159–169

    CAS  PubMed  Google Scholar 

  • Mukherjee R, Chaturvedi P, Qin HY et al (2003b) CD4+CD25+ regulatory T cells generated in response to insulin B:9-23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells. J Autoimmun 21:221–237

    Article  CAS  PubMed  Google Scholar 

  • Mukherjee R, Wagar D, Stephens TA et al (2005) Identification of CD4+ T cell-specific epitopes of islet-specific glucose-6-phosphatase catalytic subunit-related protein: a novel beta cell autoantigen in type 1 diabetes. J Immunol 174:5306–5315

    Article  CAS  PubMed  Google Scholar 

  • Murai M, Turovskaya O, Kim G et al (2009) Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 10:1178–1184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peakman M, von Herrath M (2010) Antigen-specific immunotherapy for type 1 diabetes: maximizing the potential. Diabetes 59:2087–2093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pot C, Apetoh L, Kuchroo VK (2011) Type 1 regulatory T cells (Tr1) in autoimmunity. Semin Immunol 23:202–208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Quinn A, McInerney B, Reich EP et al (2001) Regulatory and effector CD4 T cells in nonobese diabetic mice recognize overlapping determinants on glutamic acid decarboxylase and use distinct V beta genes. J Immunol 166:2982–2991

    Article  CAS  PubMed  Google Scholar 

  • Rabinovitch A (2003) Immunoregulation by cytokines in autoimmune diabetes. Adv Exp Med Biol 520:159–193

    Article  CAS  PubMed  Google Scholar 

  • Rabinovitch A, Suarez-Pinzon WL (2007) Roles of cytokines in the pathogenesis and therapy of type 1 diabetes. Cell Biochem Biophys 48:159–163

    Article  CAS  PubMed  Google Scholar 

  • Rabinovitch A, Suarez-Pinzon WL, Sorensen O et al (1997) TNF-alpha down-regulates type 1 cytokines and prolongs survival of syngeneic islet grafts in nonobese diabetic mice. J Immunol 159:6298–6303

    CAS  PubMed  Google Scholar 

  • Richer MJ, Straka N, Fang D et al (2008) Regulatory T-cells protect from type 1 diabetes after induction by coxsackievirus infection in the context of transforming growth factor-beta. Diabetes 57:1302–1311

    Article  CAS  PubMed  Google Scholar 

  • Roep BO, Peakman M (2012) Antigen targets of type 1 diabetes autoimmunity. Cold Spring Harb Perspect Med 2:a007781

    Article  PubMed  PubMed Central  Google Scholar 

  • Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562

    Article  CAS  PubMed  Google Scholar 

  • Sanjabi S, Oh SA, Li MO (2017) Regulation of the immune response by TGF-β: from conception to autoimmunity and infection. Cold Spring Harb Perspect Biol 9:a022236

    Article  PubMed  Google Scholar 

  • Serra P, Santamaria P (2015) Nanoparticle-based autoimmune disease therapy. Clin Immunol 160:3–13

    Article  CAS  PubMed  Google Scholar 

  • Singh B, Nikoopour E, Huszarik K et al (2011) Immunomodulation and regeneration of islet Beta cells by cytokines in autoimmune type 1 diabetes. J Interferon Cytokine Res 31:711–719

    Article  CAS  PubMed  Google Scholar 

  • Singh B, Schwartz JA, Sandrock C et al (2013) Modulation of autoimmune diseases by interleukin (IL)-17 producing regulatory T helper (Th17) cells. Indian J Med Res 138:591–594

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stritesky GL, Jameson SC, Hogquist KA (2012) Selection of self-reactive T cells in the thymus. Annu Rev Immunol 30:95–114

    Article  CAS  PubMed  Google Scholar 

  • Strober W, Kelsall B, Fuss I et al (1997) Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunol Today 18:61–64

    Article  CAS  PubMed  Google Scholar 

  • Suarez-Pinzon WL, Rabinovitch A (2001) Approaches to type 1 diabetes prevention by intervention in cytokine immunoregulatory circuits. Int J Exp Diabetes Res 2:3–17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tisch R, Yang XD, Singer SM et al (1993) Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature 366:72–75

    Article  CAS  PubMed  Google Scholar 

  • Tisch R, Wang B, Atkinson MA et al (2001) A glutamic acid decarboxylase 65-specific Th2 cell clone immunoregulates autoimmune diabetes in nonobese diabetic mice. J Immunol 166:6925–6936

    Article  CAS  PubMed  Google Scholar 

  • Travis MA, Sheppard D (2014) TGF-β activation and function in immunity. Annu Rev Immunol 32:51–82

    Article  CAS  PubMed  Google Scholar 

  • Walker LS, von Herrath M (2016) CD4 T cell differentiation in type 1 diabetes. Clin Exp Immunol 183:16–29

    Article  CAS  PubMed  Google Scholar 

  • Wan YY, Flavell RA (2006) The roles for cytokines in the generation and maintenance of regulatory T cells. Immunol Rev 212:114–130

    Article  CAS  PubMed  Google Scholar 

  • Wong CP, Li L, Frelinger JA et al (2006) Early autoimmune destruction of islet grafts is associated with a restricted repertoire of IGRP-specific CD8+ T cells in diabetic nonobese diabetic mice. J Immunol 176:1637–1644

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Danke NA, Berger D et al (2006) Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects. J Immunol 176:2781–2789

    Article  CAS  PubMed  Google Scholar 

  • Yang J, James EA, Sanda S et al (2013a) CD4+ T cells recognize diverse epitopes within GAD65: implications for repertoire development and diabetes monitoring. Immunology 138:269–279

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang T, Hohenstein AC, Lee CE et al (2013b) Mapping I-A(g7) restricted epitopes in murine G6PC2. Immunol Res 55:91–99

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • You S, Thieblemont N, Alyanakian MA et al (2006) Transforming growth factor-beta and T-cell-mediated immunoregulation in the control of autoimmune diabetes. Immunol Rev 212:185–202

    Article  CAS  PubMed  Google Scholar 

  • Zechel MA, Chaturvedi P, Singh B (1997) Characterization of immunodominant peptide determinants of IDDM-associated autoantigens in the NOD mouse. Res Immunol 148:338–348

    Article  CAS  PubMed  Google Scholar 

  • Zechel MA, Elliott JF, Atkinson MA et al (1998a) Characterization of novel T-cell epitopes on 65 kDa and 67 kDa glutamic acid decarboxylase relevant in autoimmune responses in NOD mice. J Autoimmun 11:83–95

    Article  CAS  PubMed  Google Scholar 

  • Zechel MA, Krawetz MD, Singh B (1998b) Epitope dominance: evidence for reciprocal determinant spreading to glutamic acid decarboxylase in non-obese diabetic mice. Immunol Rev 164:111–118

    Article  CAS  PubMed  Google Scholar 

  • Zeng H, Zhang R, Jin B et al (2015) Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol Immunol 12:566–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou X, Bailey-Bucktrout SL, Jeker LT et al (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10:1000–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Studies in our laboratories were supported by grants from the Canadian Institutes of Health Research (CIHR) (to BS) and by NIH-DK-27722 (to EHL). We thank Olga Krougly (UWO) and Steve Langley for technical support (JAX).

Author information

Authors and Affiliations

  1. Department of Microbiology & Immunology, Centre for Human Immunology, University of Western Ontario, London, ON, N6A 5C1, Canada

    Bhagirath Singh & Kelly L. Summers

  2. Department of Microbiology and Immunology, University of Western Ontario, London, ON, N6A 5C1, Canada

    Bhagirath Singh, Michael D. Krawetz, Rachel M. De Lima, Rinee Mukherjee, Pratibha Chaturvedi, Edwin Lee-Chan & Kelly L. Summers

  3. Robarts Research Institute, University of Western Ontario, London, ON, N6A 5B7, Canada

    Bhagirath Singh

  4. The Jackson Laboratory, Bar Harbor, ME, 04609, USA

    Edward H. Leiter

  5. Lawson Health Research Institute, London, ON, Canada

    Kelly L. Summers

Authors
  1. Bhagirath Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael D. Krawetz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachel M. De Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rinee Mukherjee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pratibha Chaturvedi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edwin Lee-Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edward H. Leiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kelly L. Summers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bhagirath Singh.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, B., Krawetz, M.D., De Lima, R.M. et al. Role of TGF-β in Self-Peptide Regulation of Autoimmunity. Arch. Immunol. Ther. Exp. 66, 11–19 (2018). https://doi.org/10.1007/s00005-017-0482-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-017-0482-6

Keywords

Search

Navigation