Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Adoptively transferred donor IL-17-producing CD4+ T cells augment, but IL-17 alleviates, acute graft-versus-host disease

Abstract

The role of IL-17 and IL-17-producing CD4+ T cells in acute graft-versus-host disease (GVHD) has been controversial in recent mouse and human studies. We carried out studies in a murine acute GVHD model of fully major histocompatibility complex-mismatched myeloablative bone marrow transplantation. We showed that donor wild-type CD4+ T cells exacerbated acute GVHD compared with IL-17−/− CD4+ T cells, while IL-17 reduced the severity of acute GVHD. The augmentation of acute GVHD by transferred donor IL-17-producing CD4+ T cells was associated with increased Th1 responses, while IL-17 decreased the percentages of Th1 cells in the GVHD target organs. Furthermore, IL-17 reduced the infiltration of macrophages into the GVHD tissues. In vitro study showed that IL-17 could downregulate Th1 responses, possibly through inhibiting IL-12 production by donor macrophages. Depletion of macrophages in vivo diminished the protective effect of IL-17. Our results demonstrated the differential roles of adoptively transferred donor IL-17-producing CD4+ T cells and IL-17 in the same acute GVHD model.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Coghill JM, Sarantopoulos S, Moran TP, Murphy WJ, Blazar BR, Serody JS . Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new. Blood 2011; 117: 3268–3276.

    Article  CAS  Google Scholar 

  2. Teshima T . [Pathogenesis and treatment of graft-versus-host disease]. Nihon Rinsho 2012; 70 (Suppl 2): 264–268.

    PubMed  Google Scholar 

  3. Szebeni J, Wang MG, Pearson DA, Szot GL, Sykes M . IL-2 inhibits early increases in serum gamma interferon levels associated with graft-versus-host-disease. Transplantation 1994; 58: 1385–1393.

    CAS  PubMed  Google Scholar 

  4. Mowat AM . Antibodies to IFN-gamma prevent immunologically mediated intestinal damage in murine graft-versus-host reaction. Immunology 1989; 68: 18–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Murphy WJ, Welniak LA, Taub DD, Wiltrout RH, Taylor PA, Vallera DA et al. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest 1998; 102: 1742–1748.

    Article  CAS  Google Scholar 

  6. Emmanouilides CE, Luo J, Baldwin G, Buckley D, Lau P, Lopez E et al. Murine IL-10 fails to reduce GVHD despite inhibition of alloreactivity in vitro. Bone Marrow Transplant 1996; 18: 369–375.

    CAS  PubMed  Google Scholar 

  7. Korn T, Bettelli E, Oukka M, Kuchroo VK . IL-17 and Th17 Cells. Annu Rev Immunol 2009; 27: 485–517.

    Article  CAS  Google Scholar 

  8. Yi T, Zhao D, Lin CL, Zhang C, Chen Y, Todorov I et al. Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 2008; 112: 2101–2110.

    Article  CAS  Google Scholar 

  9. Kappel LW, Goldberg GL, King CG, Suh DY, Smith OM, Ligh C et al. IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 2009; 113: 945–952.

    Article  CAS  Google Scholar 

  10. Carlson MJ, West ML, Coghill JM, Panoskaltsis-Mortari A, Blazar BR, Serody JS . In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 2009; 113: 1365–1374.

    Article  CAS  Google Scholar 

  11. Iclozan C, Yu Y, Liu C, Liang Y, Yi T, Anasetti C et al. T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol Blood Marrow Transplant 2010; 16: 170–178.

    Article  CAS  Google Scholar 

  12. Fulton LM, Carlson MJ, Coghill JM, Ott LE, West ML, Panoskaltsis-Mortari A et al. Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORgammat. J Immunol 2012; 189: 1765–1772.

    Article  CAS  Google Scholar 

  13. Yu Y, Wang D, Liu C, Kaosaard K, Semple K, Anasetti C et al. Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORgammat in mice. Blood 2011; 118: 5011–5020.

    Article  CAS  Google Scholar 

  14. Zhao XY, Xu LL, Lu SY, Huang XJ . IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. Eur J Immunol 2011; 41: 514–526.

    Article  CAS  Google Scholar 

  15. Liu Y, Cai Y, Dai L, Chen G, Ma X, Wang Y et al. The expression of Th17-associated cytokines in human acute graft-versus-host disease. Biol Blood Marrow Transplant 2013; 19: 1421–1429.

    Article  CAS  Google Scholar 

  16. Dander E, Balduzzi A, Zappa G, Lucchini G, Perseghin P, Andre V et al. Interleukin-17-producing T-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation. Transplantation 2009; 88: 1261–1272.

    Article  CAS  Google Scholar 

  17. Broady R, Yu J, Chow V, Tantiworawit A, Kang C, Berg K et al. Cutaneous GVHD is associated with the expansion of tissue-localized Th1 and not Th17 cells. Blood 2010; 116: 5748–5751.

    Article  CAS  Google Scholar 

  18. Ratajczak P, Janin A, Peffault de Latour R, Leboeuf C, Desveaux A, Keyvanfar K et al. Th17/Treg ratio in human graft-versus-host disease. Blood 2010; 116: 1165–1171.

    Article  CAS  Google Scholar 

  19. Liang Y, Ma S, Zhang Y, Wang Y, Cheng Q, Wu Y et al. IL-1beta and TLR4 signaling are involved in the aggravated murine acute graft-versus-host disease caused by delayed bortezomib administration. J Immunol 2014; 192: 1277–1285.

    Article  CAS  Google Scholar 

  20. Sun K, Wilkins DE, Anver MR, Sayers TJ, Panoskaltsis-Mortari A, Blazar BR et al. Differential effects of proteasome inhibition by bortezomib on murine acute graft-versus-host disease (GVHD): delayed administration of bortezomib results in increased GVHD-dependent gastrointestinal toxicity. Blood 2005; 106: 3293–3299.

    Article  CAS  Google Scholar 

  21. Hu B, Bao G, Zhang Y, Lin D, Wu Y, Wu D et al. Donor NK Cells and IL-15 promoted engraftment in nonmyeloablative allogeneic bone marrow transplantation. J Immunol 2012; 189: 1661–1670.

    Article  CAS  Google Scholar 

  22. Montufar-Solis D, Klein JR . An improved method for isolating intraepithelial lymphocytes (IELs) from the murine small intestine with consistently high purity. J Immunol Methods 2006; 308: 251–254.

    Article  CAS  Google Scholar 

  23. Weigmann B, Tubbe I, Seidel D, Nicolaev A, Becker C, Neurath MF . Isolation and subsequent analysis of murine lamina propria mononuclear cells from colonic tissue. Nat Protoc 2007; 2: 2307–2311.

    Article  CAS  Google Scholar 

  24. Cooke KR, Hill GR, Crawford JM, Bungard D, Brinson YS, Delmonte J Jr et al. Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest 1998; 102: 1882–1891.

    Article  CAS  Google Scholar 

  25. Anderson BE, McNiff JM, Jain D, Blazar BR, Shlomchik WD, Shlomchik MJ . Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood 2005; 105: 2227–2234.

    Article  CAS  Google Scholar 

  26. Nakae S, Iwakura Y, Suto H, Galli SJ . Phenotypic differences between Th1 and Th17 cells and negative regulation of Th1 cell differentiation by IL-17. J Leukoc Biol 2007; 81: 1258–1268.

    Article  CAS  Google Scholar 

  27. Ma S, Cheng Q, Cai Y, Gong H, Wu Y, Yu X et al. IL-17 A produced by gammadelta T cells promotes tumor growth in hepatocellular carcinoma. Cancer Res 2014; 74: 1969–1982.

    Article  CAS  Google Scholar 

  28. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE et al. IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 2007; 8: 369–377.

    Article  CAS  Google Scholar 

  29. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO et al. Late developmental plasticity in the T helper 17 lineage. Immunity 2009; 30: 92–107.

    Article  CAS  Google Scholar 

  30. Lexberg MH, Taubner A, Forster A, Albrecht I, Richter A, Kamradt T et al. Th memory for interleukin-17 expression is stable in vivo. Eur J Immunol 2008; 38: 2654–2664.

    Article  CAS  Google Scholar 

  31. Serody JS, Hill GR . The IL-17 differentiation pathway and its role in transplant outcome. Biol Blood Marrow Transplant 2012; 18 (1 Suppl): S56–S61.

    Article  CAS  Google Scholar 

  32. Ciric B, El-behi M, Cabrera R, Zhang GX, Rostami A . IL-23 drives pathogenic IL-17-producing CD8+ T cells. J Immunol 2009; 182: 5296–5305.

    Article  CAS  Google Scholar 

  33. Kondo T, Takata H, Matsuki F, Takiguchi M . Cutting edge: phenotypic characterization and differentiation of human CD8+ T cells producing IL-17. J Immunol 2009; 182: 1794–1798.

    Article  CAS  Google Scholar 

  34. Roark CL, Simonian PL, Fontenot AP, Born WK, O'Brien RL . gammadelta T cells: an important source of IL-17. Curr Opin Immunol 2008; 20: 353–357.

    Article  CAS  Google Scholar 

  35. Soumelis V . NRP-1 and IL-17-producing NKT cells. Blood 2011; 118: 2934–2935.

    Article  CAS  Google Scholar 

  36. Michel ML, Mendes-da-Cruz D, Keller AC, Lochner M, Schneider E, Dy M et al. Critical role of ROR-gammat in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc Natl Acad Sci USA 2008; 105: 19845–19850.

    Article  CAS  Google Scholar 

  37. Ferrara JL . The cytokine modulation of acute graft-versus-host disease. Bone Marrow Transplant 1998; 21 (Suppl 3): S13–S15.

    PubMed  Google Scholar 

  38. Becker C, Dornhoff H, Neufert C, Fantini MC, Wirtz S, Huebner S et al. Cutting edge: IL-23 cross-regulates IL-12 production in T cell-dependent experimental colitis. J Immunol 2006; 177: 2760–2764.

    Article  CAS  Google Scholar 

  39. Sieve AN, Meeks KD, Lee S, Berg RE . A novel immunoregulatory function for IL-23: Inhibition of IL-12-dependent IFN-gamma production. Eur J Immunol 2010; 40: 2236–2247.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Ziling Zhu of Soochow University for irradiation of the mice. This work has been supported by grants from the National Natural Science Foundation of China (81273268, 81471586, 81273259, 81471589 and 81500145), the Natural Science Foundation of Jiangsu Province (BK20150352), project funding from Suzhou city (SWG0904), and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Author contributions

H-YL and D-PW designed the study; Y-FC, S-BM and Y-JL performed the experiments; H-LG, QC, BH, YW and XY contributed to the experiments; CD provided the IL-17−/− mice and reviewed the manuscript; Y-FC, S-BM, Y-JL, KS and H-YL analyzed the data; and Y-FC, S-BM and H-YL wrote the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Depei Wu or Haiyan Liu.

Ethics declarations

Competing interests

CD has honoraria from the Speakers Bureau of Bristol-Myers Squibb and is a consultant/advisory board member of GlaxoSmithKline. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information for this article can be found on the Cellular & Molecular Immunology website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cai, Y., Ma, S., Liu, Y. et al. Adoptively transferred donor IL-17-producing CD4+ T cells augment, but IL-17 alleviates, acute graft-versus-host disease. Cell Mol Immunol 15, 233–245 (2018). https://doi.org/10.1038/cmi.2016.37

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/cmi.2016.37

Keywords

This article is cited by

Search

Quick links