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Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model

Cellular & Molecular Immunology volume 9, pages 455–463 (2012)Cite this article

Abstract

Previously, we established a model in which physiologically adequate function of the autologous β cells was recovered in non-obese diabetic (NOD) mice after the onset of hyperglycemia by rendering them hemopoietic chimera. These mice were termed antea-diabetic. In the current study, we addressed the role of T regulatory (Treg) cells in the mechanisms mediating the restoration of euglycemia in the antea-diabetic NOD model. The data generated in this study demonstrated that the numbers of Treg cells were decreased in unmanipulated NOD mice, with the most profound deficiency detected in the pancreatic lymph nodes (PLNs). The impaired retention of the Treg cells in the PLNs correlated with the locally compromised profile of the chemokines involved in their trafficking, with the most prominent decrease observed in SDF-1. The amelioration of autoimmunity and restoration of euglycemia observed in the antea-diabetic mice was associated with restoration of the Treg cell population in the PLNs. These data indicate that the function of the SDF-1/CXCR4 axis and the retention of Treg cells in the PLNs have a potential role in diabetogenesis and in the amelioration of autoimmunity and β cell regeneration in the antea-diabetic model. We have demonstrated in the antea-diabetic mouse model that lifelong recovery of the β cells has a strong correlation with normalization of the Treg cell population in the PLNs. This finding offers new opportunities for testing the immunomodulatory regimens that promote accumulation of Treg cells in the PLNs as a therapeutic approach for type 1 diabetes (T1D).

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References

  1. Kleiner IS, Meltzer SJ . Retention in the circulation of dextrose in normal and depancreatized animals, and the effect of an intravenous injection of an emulsion of pancreas upon this retention. Proc Natl Acad Sci USA 1915; 1: 338–341.

    Article  CAS  Google Scholar 

  2. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA . Pancreatic extracts in the treatment of diabetes mellitus: preliminary report. 1922. CMAJ 1991; 145: 1281–1286.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Lacy PE, Kostianovsky M . Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 1967; 16: 35–39.

    Article  CAS  Google Scholar 

  4. Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343: 230–238.

    Article  CAS  Google Scholar 

  5. Selam JL . External and implantable insulin pumps: current place in the treatment of diabetes. Exp Clin Endocrinol Diabetes 2001; 109( Suppl 2): S333–S340.

    Article  CAS  Google Scholar 

  6. Tanna S, Joan Taylor M, Sahota TS, Sawicka K . Glucose-responsive UV polymerised dextran-concanavalin A acrylic derivatised mixtures for closed-loop insulin delivery. Biomaterials 2006; 27: 1586–1597.

    Article  CAS  Google Scholar 

  7. Gepts W . 1965. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 1965; 14: 619–633.

    Article  CAS  Google Scholar 

  8. Ogawa N, List JF, Habener JF, Maki T . Cure of overt diabetes in NOD mice by transient treatment with anti-lymphocyte serum and exendin-4. Diabetes 2004; 53: 1700–1705.

    Article  CAS  Google Scholar 

  9. Suri A, Calderon B, Esparza TJ, Frederick K, Bittner B, Unanue ER . Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006; 311: 1778–1780.

    Article  CAS  Google Scholar 

  10. Sherry NA, Chen W, Kushner JA, Glandt M, Tang Q, Tsai S et al. Exendin-4 improves reversal of diabetes in NOD mice treated with anti-CD3 monoclonal antibody by enhancing recovery of beta-cells. Endocrinology 2007; 148: 5136–5144.

    Article  CAS  Google Scholar 

  11. Weir GC, Bonner-Weir S . Dreams for type 1 diabetes: shutting off autoimmunity and stimulating beta-cell regeneration. Endocrinology 2010; 151: 2971–2973.

    Article  CAS  Google Scholar 

  12. Alipio Z, Liao W, Roemer EJ, Waner M, Fink LM, Ward DC et al. Reversal of hyperglycemia in diabetic mouse models using induced-pluripotent stem (iPS)-derived pancreatic beta-like cells. Proc Natl Acad Sci USA 2010; 107: 13426–13431.

    Article  CAS  Google Scholar 

  13. Tsai S, Shameli A, Yamanouchi J, Clemente-Casares X, Wang J, Serra P et al. Reversal of autoimmunity by boosting memory-like autoregulatory T cells. Immunity 2010; 32: 568–580.

    Article  CAS  Google Scholar 

  14. Chatenoud L, Thervet E, Primo L, Bach JF . Anti-CD3 antibody induces long-term remission of overt autoimmunity in nonobese diabetic mice. Proc Natl Acad Sci USA 1994; 91: 123–127.

    Article  CAS  Google Scholar 

  15. Serreze DV, Gaedeke JW, Leiter EH . Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C. Proc Natl Acad Sci USA 1993; 90: 9625–9629.

  16. Zorina TD, Kaufman CL, Ildstad ST . Mixed allogeneic chimerism for the prevention of autoimmune diabetes, and the reversal of insulitis in the non-obese diabetic (NOD) mouse. J Immunol 1993; 150( 8 part II): A80

    Google Scholar 

  17. Li H, Kaufman CL, Boggs SS, Johnson PC, Patrene KD, Ildstad ST . Mixed allogeneic chimerism induced by a sublethal approach prevents autoimmune diabetes and reverses insulitis in nonobese diabetic (NOD) mice. J Immunol 1996; 156: 380–388.

    CAS  PubMed  Google Scholar 

  18. Zorina TD, Subbotin VM, Bertera S, Alexander AM, Haluszczak C, Gambrell B et al. Recovery of the endogenous beta cell function in the NOD model of autoimmune diabetes. Stem Cells 2003; 21: 377–388.

    Article  Google Scholar 

  19. Tian B, Hao J, Zhang Y, Tian L, Yi H, O'Brien TD et al. Upregulating CD4+CD25+FOXP3+ regulatory T cells in pancreatic lymph nodes in diabetic NOD mice by adjuvant immunotherapy. Transplantation 2009; 87: 198–206.

    Article  CAS  Google Scholar 

  20. Kim JM, Rasmussen JP, Rudensky AY . Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol 2007; 8: 191–197.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  22. Homann D, von Herrath M . Regulatory T cells and type 1 diabetes. Clin Immunol 2004; 112: 202–209.

    Article  CAS  Google Scholar 

  23. Jaeckel E, von Boehmer H, Manns MP . Antigen-specific FoxP3-transduced T-cells can control established type 1 diabetes. Diabetes 2005; 54: 306–310.

    Article  CAS  Google Scholar 

  24. D'Alise AM, Auyeung V, Feuerer M, Nishio J, Fontenot J, Benoist C et al. The defect in T-cell regulation in NOD mice is an effect on the T-cell effectors. Proc Natl Acad Sci USA 2008; 105: 19857–19862.

    Article  CAS  Google Scholar 

  25. Tritt M, Sgouroudis E, d'Hennezel E, Albanese A, Piccirillo CA . Functional waning of naturally occurring CD4+ regulatory T-cells contributes to the onset of autoimmune diabetes. Diabetes 2008; 57: 113–123.

    Article  CAS  Google Scholar 

  26. Aboumrad E, Madec AM, Thivolet C . The CXCR4/CXCL12 (SDF-1) signalling pathway protects non-obese diabetic mouse from autoimmune diabetes. Clin Exp Immunol 2007; 148: 432–439.

    Article  CAS  Google Scholar 

  27. Aspord C, Czerkinsky C, Durand A, Stefanutti A, Thivolet C . Alpha4 integrins and L-selectin differently orchestrate T-cell activity during diabetes prevention following oral administration of CTB-insulin. J. Autoimmun 2002; 19: 223–232.

    Article  Google Scholar 

  28. Leng Q, Nie Y, Zou Y, Chen J . Elevated CXCL12 expression in the bone marrow of NOD mice is associated with altered T cell and stem cell trafficking and diabetes development. BMC Immunol 2008; 9: 51.

    Article  Google Scholar 

  29. Szalai C, Csaszar A, Czinner A, Szabo T, Panczel P, Madacsy L et al. Chemokine receptor CCR2 and CCR5 polymorphisms in children with insulin-dependent diabetes mellitus. Pediatr Res 199; 46: 82–84.

    Article  Google Scholar 

  30. Tonkin DR, Haskins K . Regulatory T cells enter the pancreas during suppression of type 1 diabetes and inhibit effector T cells and macrophages in a TGF-beta-dependent manner. Eur J Immunol 2008; 39: 1313–1322.

    Article  Google Scholar 

  31. Ildstad ST, Wren SM, Bluestone JA, Barbieri SA, Sachs DH . Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance. J Exp Med 1985; 162: 231–244.

    Article  CAS  Google Scholar 

  32. Zorina TD, Subbotin VM, Bertera S, Alexander AM, Haluszczak C, Styche AJ et al. Distinct characteristics and features of allogeneic chimerism in the NOD mouse model of autoimmune diabetes. Cell Transplant 2002; 11: 113–123.

    Article  Google Scholar 

  33. Soderstrom I, Bergman ML, Colucci F, Lejon K, Bergqvist I, Holmberg D . Establishment and characterization of RAG-2 deficient non-obese diabetic mice. Scand J Immunol 1996; 43: 525–530.

    Article  CAS  Google Scholar 

  34. Fontenot JD, Gavin MA, Rudensky AY . Foxp3 programs the development and function of CD4+CD25+ regulatory cells. Nat Immunol 2003; 4: 330–336.

    Article  CAS  Google Scholar 

  35. Kukreja A, Cost G, Marker J, Zhang C, Sun Z, Lin-Su K et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest 2002; 109: 131–140.

    Article  CAS  Google Scholar 

  36. Putnam AL, Vendrame F, Dotta F, Gottlieb PA . CD4+CD25high regulatory T cells in human autoimmune diabetes. J Autoimmun 2005; 24: 55–62.

    Article  CAS  Google Scholar 

  37. Brusko T, Wasserfall C, McGrail K, Schatz R, Viener HL, Schatz D et al. No alterations in the frequency of FOXP3+ regulatory T-cells in type 1 diabetes. Diabetes 2007; 56: 604–612.

    Article  CAS  Google Scholar 

  38. Hoglund P, Mintern J, Waltzinger C, Heath W, Benoist C, Mathis D . Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J Exp Med 1999; 189: 331–339.

    Article  CAS  Google Scholar 

  39. Gregori S, Giarratana N, Smiroldo S, Adorini L . Dynamics of pathogenic and suppressor T cells in autoimmune diabetes development. J Immunol 2003; 171: 4040–4047.

    Article  CAS  Google Scholar 

  40. Dubois-Laforgue D, Hendel H, Caillat-Zucman S, Zagury JF, Winkler C, Boitard C et al. A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes. Diabetes 2001; 50: 1211–1213.

    Article  CAS  Google Scholar 

  41. Ide A, Kawasaki E, Abiru N, Sun F, Fukushima T, Takahashi R et al. Stromal-cell derived factor-1 chemokine gene variant is associated with type 1 diabetes age at onset in Japanese population. Hum Immunol 2003; 64: 973–978.

    Article  CAS  Google Scholar 

  42. Ara T, Tokoyoda K, Sugiyama T, Egawa T, Kawabata K, Nagasawa T . Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 2003; 19: 257–267.

    Article  CAS  Google Scholar 

  43. Seung E, Iwakoshi N, Woda BA, Markees TG, Mordes JP, Rossini AA et al. Allogeneic hematopoietic chimerism in mice treated with sublethal myeloablation and anti-CD154 antibody: absence of graft-versus-host disease, induction of skin allograft tolerance, and prevention of recurrent autoimmunity in islet-allografted NOD/Lt mice. Blood 2000; 95: 2175–2182.

    CAS  PubMed  Google Scholar 

  44. Belghith M, Bluestone JA, Barriot S, Megret J, Bach JF, Chatenoud L . TGF-beta-dependent mechanisms mediate restoration of self-tolerance induced by antibodies to CD3 in overt autoimmune diabetes. Nat Med 2003; 9: 1202–1208.

    Article  CAS  Google Scholar 

  45. Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM . CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004; 199: 1467–1477.

    Article  CAS  Google Scholar 

  46. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; 199: 1455–1465.

    Article  CAS  Google Scholar 

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Acknowledgements

Grants from Juvenile Diabetes Research Foundation, JDRF #1-2004-580 (T.Z.) and JDRF # 7-2005-1154 (M.T. and T.Z.) and Grant from Intramural Grant Program, Jefferson School of Health Professions, Thomas Jefferson University, 2010-2011 (T.Z.) supported this study.

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Authors and Affiliations

  1. Indiana University School of Medicine, Indianapolis, IN, USA

    Benjamin K Nti

  2. Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Janet L Markman

  3. Division of Immunogenetics, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Suzanne Bertera, Alexis J Styche, Robert J Lakomy & Massimo Trucco

  4. Independent investigator 602 Samuel Dr., Madison, WI, USA

    Vladimir M Subbotin

  5. Department of Bioscience Technologies, Jefferson School of Health Professions, Thomas Jefferson University, Philadelphia, PA, USA

    Tatiana D Zorina

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  1. Benjamin K Nti
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Correspondence to Tatiana D Zorina.

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Nti, B., Markman, J., Bertera, S. et al. Treg cells in pancreatic lymph nodes: the possible role in diabetogenesis and β cell regeneration in a T1D model. Cell Mol Immunol 9, 455–463 (2012). https://doi.org/10.1038/cmi.2012.36

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