Diabetologia

, Volume 60, Issue 12, pp 2409–2417 | Cite as

Differential modulation of IL-12 family cytokines in autoimmune islet graft failure in mice

  • Feng-Cheng Chou
  • Heng-Yi Chen
  • Hsin-Hui Chen
  • Gu-Jiun Lin
  • Shih-Hua Lin
  • Huey-Kang Sytwu
Article

Abstract

Aims/hypothesis

The relative contribution of T helper (Th)1 and Th17 cells in graft rejection is inconclusive, on the basis of evidence provided by different T cell-related cytokine-deficient animal models and graft types.

Methods

We used novel antigen-presenting-cell-specific Il-12p35 (also known as Il12a)-knockout (KO), IL-23p19-knockdown (KD) and IL-27p28-KD strategies to investigate T cell differentiation in islet graft rejection.

Results

In vitro dendritic cell–T cell coculture experiments revealed that dendritic cells from Il-12p35-KO and IL-23p19-KD mice showed reduced ability to stimulate IFN-γ and IL-17 production in T cells, respectively. To further explore the T cell responses in islet graft rejection, we transplanted islets into streptozotocin-induced diabetic NOD/severe combined immunodeficiency (SCID) recipient mice with IL-12-, IL-23-, or IL-27-deficient backgrounds and then challenged them with NOD.BDC2.5 T cells. The survival of islet grafts was significantly prolonged in Il-12p35-KO and IL-23p19-KD recipients compared with the control recipients. T cell infiltrations and Th1 cell populations were also decreased in the grafts, correlating with prolonged graft survival.

Conclusions/interpretation

Our results suggest that IL-12 and IL-23 promote and/or maintain Th1 cell-mediated islet graft rejection. Thus, blockade of IL-12 and IL-23 might act as therapeutic strategies for reducing rejection responses.

Keywords

Graft rejection IL-12 IL-23 Islet transplantation Th1 Th17 

Abbreviations

APC

Antigen-presenting cell

BMDC

Bone-marrow-derived dendritic cell

GIC

Graft-infiltrating cell

KD

Knockdown

KO

Knockout

PLN

Pancreatic lymph node

PRR

Pattern-recognition receptor

SCID

Severe combined immunodeficiency

Th

T helper

TLR

Toll-like receptor

Treg

Regulatory T

WT

Wild-type

Supplementary material

125_2017_4418_MOESM1_ESM.pdf (437 kb)
ESM(PDF 436 kb)

References

  1. 1.
    Takeuchi T, Lowry RP, Konieczny B (1992) Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance. Transplantation 53:1281–1294CrossRefPubMedGoogle Scholar
  2. 2.
    Sayegh MH, Akalin E, Hancock WW et al (1995) CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. J Exp Med 181:1869–1874CrossRefPubMedGoogle Scholar
  3. 3.
    Nickerson P, Pacheco-Silva A, O'Connell PJ, Steurer W, Kelley VR, Strom TB (1993) Analysis of cytokine transcripts in pancreatic islet cell allografts during rejection and tolerance induction. Transplant Proc 25:984–985PubMedGoogle Scholar
  4. 4.
    Mottram PL, Han WR, Purcell LJ, McKenzie IF, Hancock WW (1995) Increased expression of IL-4 and IL-10 and decreased expression of IL-2 and interferon-gamma in long-surviving mouse heart allografts after brief CD4-monoclonal antibody therapy. Transplantation 59:559–565CrossRefPubMedGoogle Scholar
  5. 5.
    Hancock WW, Sayegh MH, Kwok CA, Weiner HL, Carpenter CB (1993) Oral, but not intravenous, alloantigen prevents accelerated allograft rejection by selective intragraft Th2 cell activation. Transplantation 55:1112–1118CrossRefPubMedGoogle Scholar
  6. 6.
    Strom TB, Roy-Chaudhury P, Manfro R et al (1996) The Th1/Th2 paradigm and the allograft response. Curr Opin Immunol 8:688–693CrossRefPubMedGoogle Scholar
  7. 7.
    Steiger J, Nickerson PW, Steurer W, Moscovitch-Lopatin M, Strom TB (1995) IL-2 knockout recipient mice reject islet cell allografts. J Immunol 155:489–498PubMedGoogle Scholar
  8. 8.
    Raisanen-Sokolowski A, Mottram PL, Glysing-Jensen T, Satoskar A, Russell ME (1997) Heart transplants in interferon-gamma, interleukin 4, and interleukin 10 knockout mice. Recipient environment alters graft rejection. J Clin Invest 100:2449–2456CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 6:1142–1151CrossRefPubMedGoogle Scholar
  10. 10.
    Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ (2005) IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 201:1925–1935CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Yuan X, Paez-Cortez J, Schmitt-Knosalla I et al (2008) A novel role of CD4 Th17 cells in mediating cardiac allograft rejection and vasculopathy. J Exp Med 205:3133–3144CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Burrell BE, Csencsits K, Lu G, Grabauskiene S, Bishop DK (2008) CD8+ Th17 mediate costimulation blockade-resistant allograft rejection in T-bet-deficient mice. J Immunol 181:3906–3914CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Atalar K, Afzali B, Lord G, Lombardi G (2009) Relative roles of Th1 and Th17 effector cells in allograft rejection. Curr Opin Organ Transplant 14:23–29CrossRefPubMedGoogle Scholar
  14. 14.
    Liu Z, Fan H, Jiang S (2013) CD4(+) T cell subsets in transplantation. Immunol Rev 252:183–191CrossRefPubMedGoogle Scholar
  15. 15.
    Askar M (2014) T helper subsets & regulatory T cells: rethinking the paradigm in the clinical context of solid organ transplantation. Int J Immunogenet 41:185–194CrossRefPubMedGoogle Scholar
  16. 16.
    Hunter CA (2005) New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol 5:521–531CrossRefPubMedGoogle Scholar
  17. 17.
    Owaki T, Asakawa M, Morishima N et al (2005) A role for IL-27 in early regulation of Th1 differentiation. J Immunol 175:2191–2200CrossRefPubMedGoogle Scholar
  18. 18.
    Zhu J, Jankovic D, Oler AJ et al (2012) The transcription factor T-bet is induced by multiple pathways and prevents an endogenous Th2 cell program during Th1 cell responses. Immunity 37:660–673CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Yoshida H, Nakaya M, Miyazaki Y (2009) Interleukin 27: a double-edged sword for offense and defense. J Leukoc Biol 86:1295–1303CrossRefPubMedGoogle Scholar
  20. 20.
    Awasthi A, Carrier Y, Peron JP et al (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8:1380–1389CrossRefPubMedGoogle Scholar
  21. 21.
    Batten M, Li J, Yi S et al (2006) Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells. Nat Immunol 7:929–936CrossRefPubMedGoogle Scholar
  22. 22.
    Villarino A, Hibbert L, Lieberman L et al (2003) The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19:645–655CrossRefPubMedGoogle Scholar
  23. 23.
    Hung JT, Liao JH, Lin YC et al (2005) Immunopathogenic role of TH1 cells in autoimmune diabetes: evidence from a T1 and T2 doubly transgenic non-obese diabetic mouse model. J Autoimmun 25:181–192CrossRefPubMedGoogle Scholar
  24. 24.
    Judkowski V, Pinilla C, Schroder K, Tucker L, Sarvetnick N, Wilson DB (2001) Identification of MHC class II-restricted peptide ligands, including a glutamic acid decarboxylase 65 sequence, that stimulate diabetogenic T cells from transgenic BDC2.5 nonobese diabetic mice. J Immunol 166:908–917CrossRefPubMedGoogle Scholar
  25. 25.
    Chou FC, Kuo CC, Wang YL et al (2013) Overexpression of galectin-9 in islets prolongs grafts survival via downregulation of Th1 responses. Cell Transplant 22:2135–2145CrossRefPubMedGoogle Scholar
  26. 26.
    Sabet-Baktach M, Eggenhofer E, Rovira J et al (2013) Double deficiency for RORgammat and T-bet drives Th2-mediated allograft rejection in mice. J Immunol 191:4440–4446CrossRefPubMedGoogle Scholar
  27. 27.
    Cruz A, Khader SA, Torrado E et al (2006) Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol 177:1416–1420CrossRefPubMedGoogle Scholar
  28. 28.
    Harrington LE, Hatton RD, Mangan PR et al (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132CrossRefPubMedGoogle Scholar
  29. 29.
    Oppmann B, Lesley R, Blom B et al (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725CrossRefPubMedGoogle Scholar
  30. 30.
    Grieco FA, Moore F, Vigneron F et al (2014) IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets. Diabetologia 57:502–511CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang GX, Yu S, Gran B et al (2003) Role of IL-12 receptor beta 1 in regulation of T cell response by APC in experimental autoimmune encephalomyelitis. J Immunol 171:4485–4492CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang GX, Gran B, Yu S et al (2003) Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-beta 2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system. J Immunol 170:2153–2160CrossRefPubMedGoogle Scholar
  33. 33.
    Awasthi A, Riol-Blanco L, Jager A et al (2009) Cutting edge: IL-23 receptor gfp reporter mice reveal distinct populations of IL-17-producing cells. J Immunol 182:5904–5908CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Mascanfroni ID, Yeste A, Vieira SM et al (2013) IL-27 acts on dendritic cells to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39. Nat Immunol 14:1054–1063CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Wang S, Miyazaki Y, Shinozaki Y, Yoshida H (2007) Augmentation of antigen-presenting and Th1-promoting functions of dendritic cells by WSX-1(IL-27R) deficiency. J Immunol 179:6421–6428CrossRefPubMedGoogle Scholar
  36. 36.
    Alegre ML, Chong A (2009) Toll-like receptors (TLRs) in transplantation. Front Biosci 1:36–43Google Scholar
  37. 37.
    Chen L, Wang T, Zhou P et al (2006) TLR engagement prevents transplantation tolerance. Am J Transplant 6:2282–2291CrossRefPubMedGoogle Scholar
  38. 38.
    Chen L, Ahmed E, Wang T et al (2009) TLR signals promote IL-6/IL-17-dependent transplant rejection. J Immunol 182:6217–6225CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Leemans JC, Stokman G, Claessen N et al (2005) Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney. J Clin Invest 115:2894–2903CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Lau H, Reemtsma K, Hardy MA (1984) Prolongation of rat islet allograft survival by direct ultraviolet irradiation of the graft. Science 223:607–609CrossRefPubMedGoogle Scholar
  41. 41.
    James RF, Lake SP, Chamberlain J et al (1989) Gamma irradiation of isolated rat islets pretransplantation produces indefinite allograft survival in cyclosporine-treated recipients. Transplantation 47:929–933CrossRefPubMedGoogle Scholar
  42. 42.
    Calderon B, Suri A, Miller MJ, Unanue ER (2008) Dendritic cells in islets of Langerhans constitutively present beta cell-derived peptides bound to their class II MHC molecules. Proc Natl Acad Sci U S A 105:6121–6126CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Feng-Cheng Chou
    • 1
  • Heng-Yi Chen
    • 2
  • Hsin-Hui Chen
    • 3
  • Gu-Jiun Lin
    • 4
  • Shih-Hua Lin
    • 5
  • Huey-Kang Sytwu
    • 1
    • 2
  1. 1.Department and Graduate Institute of Microbiology and ImmunologyNational Defense Medical CenterTaipei 114Taiwan
  2. 2.Graduate Institute of Life SciencesNational Defense Medical CenterTaipeiTaiwan
  3. 3.Department of MedicineNational Defense Medical CenterTaipeiTaiwan
  4. 4.Department of Biology and AnatomyNational Defense Medical CenterTaipeiTaiwan
  5. 5.Department of Internal MedicineTri-Service General Hospital, National Defense Medical CenterTaipeiTaiwan

Personalised recommendations