Skip to main content

Advertisement

SpringerLink
Log in

T Regulatory Cells in Autoimmune Diabetes: Past Challenges, Future Prospects

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

Accumulating evidence suggests that defective regulation is an essential underlying cause of autoimmunity. The development of type 1 diabetes in the NOD mouse strain it is a complex process that depends on a fine balance between pathogenic and regulatory pathways.

Discussion

We have utilized a series of transgenic and knockout mice to determine the relative importance of regulatory T cells and negative regulatory receptors on the development and progression of type 1 diabetes.

Conclusion

This review will focus on the origins and function of Treg in peripheral self-tolerance. We will summarize the role of Treg in preventing autoimmune diseases, with a particular focus on Type 1 Diabetes (T1D), and discuss the prospects for Treg-based therapies for autoimmune diseases.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Moudgil KD, Sercarz EE. The self-directed T cell repertoire: its creation and activation. Rev Immunogenet. 2000;2:26–37.

    PubMed  CAS  Google Scholar 

  2. Makino S, Kunimoto K, Muraoka Y, et al. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu. 1980;29:1–13.

    PubMed  CAS  Google Scholar 

  3. Turley S, Poirot L, Hattori M, et al. Physiological beta cell death triggers priming of self-reactive T cells by dendritic cells in a type-1 diabetes model. J Exp Med. 2003;198:1527–37.

    Article  PubMed  CAS  Google Scholar 

  4. Yu L, Robles DT, Abiru N, et al. Early expression of antiinsulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci U S A. 2000;97:1701–706.

    Article  PubMed  CAS  Google Scholar 

  5. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic 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. 1995;155:1151–64.

    PubMed  CAS  Google Scholar 

  6. Asano M, Toda M, Sakaguchi N, et al. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med. 1996;184:387–96.

    Article  PubMed  CAS  Google Scholar 

  7. Itoh M, Takahashi T, Sakaguchi N, et al. Thymus and autoimmunity: production of CD25 + CD4 + naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol. 1999;162:5317–26.

    PubMed  CAS  Google Scholar 

  8. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4 + CD25 + regulatory T cells. Nat Immunol. 2003;4:330–36.

    Article  PubMed  CAS  Google Scholar 

  9. Godfrey VL, Wilkinson JE, Rinchik EM, et al. Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: potential model for thymic education. Proc Natl Acad Sci U S A. 1991;88:5528–32.

    Article  PubMed  CAS  Google Scholar 

  10. Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002;39:537–45.

    Article  PubMed  CAS  Google Scholar 

  11. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.

    Article  PubMed  CAS  Google Scholar 

  12. Fontenot JD, Rasmussen JP, Williams LM, et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005;22:329–41.

    Article  PubMed  CAS  Google Scholar 

  13. Wicker LS, Miller BJ, Mullen Y. Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes. 1986;35:855–60.

    Article  PubMed  CAS  Google Scholar 

  14. Bendelac A, Carnaud C, Boitard C, et al. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4 + and Lyt-2 + T cells. J Exp Med. 1987;166:823–32.

    Article  PubMed  CAS  Google Scholar 

  15. Boitard C, Yasunami R, Dardenne M, et al. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med. 1989;169:1669–80.

    Article  PubMed  CAS  Google Scholar 

  16. Herbelin A, Gombert JM, Lepault F, et al. Mature mainstream TCR alpha beta + CD4 + thymocytes expressing L-selectin mediate “active tolerance” in the nonobese diabetic mouse. J Immunol. 1998;161:2620–28.

    PubMed  CAS  Google Scholar 

  17. Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4 + CD25 + immunoregulatory T cells that control autoimmune diabetes. Immunity. 2000;12:431–40.

    Article  PubMed  CAS  Google Scholar 

  18. Lenschow DJ, Herold KC, Rhee L, et al. CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity. 1996;5:285–93.

    Article  PubMed  CAS  Google Scholar 

  19. Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell. 2000;101:455–58.

    Article  PubMed  CAS  Google Scholar 

  20. Tang Q, Henriksen KJ, Boden EK, et al. Cutting edge: CD28 controls peripheral homeostasis of CD4 + CD25 + regulatory T cells. J Immunol. 2003;171:3348–52.

    PubMed  CAS  Google Scholar 

  21. Fontenot JD, Rudensky AY. Molecular aspects of regulatory T cell development. Semin Immunol. 2004;16:73–80.

    Article  PubMed  CAS  Google Scholar 

  22. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, et al. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes. 2002;51:638–45.

    Article  PubMed  CAS  Google Scholar 

  23. Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007;7:585–98.

    Article  PubMed  CAS  Google Scholar 

  24. Tang Q, Henriksen KJ, Bi M, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199:1455–65.

    Article  PubMed  CAS  Google Scholar 

  25. Masteller EL, Warner MR, Tang Q, et al. Expansion of functional endogenous antigen-specific CD4 + CD25 + regulatory T cells from nonobese diabetic mice. J Immunol. 2005;175:3053–59.

    PubMed  CAS  Google Scholar 

  26. Meagher C. J Immunol In Press: (2008).

  27. Tang Q, Bluestone JA. The FoxP3 + regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008;9:129–34.

    Article  CAS  Google Scholar 

  28. Chen W, Jin W, Hardegen N, et al. Conversion of peripheral CD4+ CD25-naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875–86.

    Article  PubMed  CAS  Google Scholar 

  29. You S, Leforban B, Garcia C, et al. Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci U S A. 2007;104:6335–40.

    Article  PubMed  CAS  Google Scholar 

  30. Bluestone JA, Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3:253–57.

    Article  PubMed  CAS  Google Scholar 

  31. Hsieh CS, Liang Y, Tyznik AJ, et al. Recognition of the peripheral self by naturally arising CD25 + CD4 + T cell receptors. Immunity. 2004;21:267–77.

    Article  PubMed  CAS  Google Scholar 

  32. Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity. 2008;28:100–11.

    Article  PubMed  CAS  Google Scholar 

  33. Izcue A, Powrie F. Special regulatory T-cell review: regulatory T cells and the intestinal tract—patrolling the frontier. Immunology. 2008;123:6–10.

    Article  PubMed  CAS  Google Scholar 

  34. Tang Q, Adams JY, Tooley AJ, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7:83–92.

    Article  PubMed  CAS  Google Scholar 

  35. Cederbom L, Hall H, Ivars F. CD4 + CD25 + regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol. 2000;30:1538–43.

    Article  PubMed  CAS  Google Scholar 

  36. Misra N, Bayry J, Lacroix-Desmazes S, et al. Cutting edge: human CD4 + CD25 + T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol. 2004;172:4676–80.

    PubMed  CAS  Google Scholar 

  37. Herman AE, Freeman GJ, Mathis D, et al. CD4+ CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J Exp Med. 2004;199:1479–89.

    Article  PubMed  CAS  Google Scholar 

  38. You S, Belghith M, Cobbold S, et al. Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes. 2005;54:1415–22.

    Article  PubMed  CAS  Google Scholar 

  39. Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006;212:217–37.

    Article  PubMed  CAS  Google Scholar 

  40. Earle KE, Tang Q, Zhou X, et al. In vitro expanded human CD4 + CD25 + regulatory T cells suppress effector T cell proliferation. Clin Immunol. 2005;115:3–9.

    Article  PubMed  CAS  Google Scholar 

  41. Kim JM, Rudensky A. The role of the transcription factor Foxp3 in the development of regulatory T cells. Immunol Rev. 2006;212:86–98.

    Article  PubMed  CAS  Google Scholar 

  42. Hill JA, Feuerer M, Tash K, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity. 2007;27:786–800.

    Article  PubMed  CAS  Google Scholar 

  43. Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4 + T reg cells. J Exp Med. 2006;203:1701–711.

    Article  PubMed  CAS  Google Scholar 

  44. Lopez M, Clarkson MR, Albin M, et al. A novel mechanism of action for anti-thymocyte globulin: induction of CD4+ CD25+ Foxp3+ regulatory T cells. J Am Soc Nephrol. 2006;17:2844–53.

    Article  PubMed  CAS  Google Scholar 

  45. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346:1692–98.

    Article  PubMed  CAS  Google Scholar 

  46. Herold KC, Gitelman SE, Masharani U, et al. A single course of anti-CD3 monoclonal antibody hOKT3gamma1 (Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes. 2005;54:1763–69.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. UCSF Diabetes Center, San Francisco, CA, 94143, USA

    Jeffrey A. Bluestone, Qizhi Tang & Caitlin E. Sedwick

Authors
  1. Jeffrey A. Bluestone
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qizhi Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Caitlin E. Sedwick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jeffrey A. Bluestone.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bluestone, J.A., Tang, Q. & Sedwick, C.E. T Regulatory Cells in Autoimmune Diabetes: Past Challenges, Future Prospects. J Clin Immunol 28, 677–684 (2008). https://doi.org/10.1007/s10875-008-9242-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-008-9242-z

Keywords

Search

Navigation