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.

  • Original Article
  • Published:

Molecular Targets for Therapy

Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease

Leukemia volume 26, pages 1471–1474 (2012)Cite this article

Subjects

Abstract

The contribution of Th17 cells in acute graft-versus-host disease (aGVHD) has been demonstrated in aGVHD mouse models. However, their contribution in human gastrointestinal aGVHD remains unclear. We evaluated Th17 cells in a cohort of 23 patients at diagnosis of aGVHD. In this study, we have shown that the absolute number of Th17 cells using the CCR6 and CD161 markers were significantly higher in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD. Moreover, in keeping with the increase of CCR6+ and CD161+ T cells, RORγt the key transcription factor that orchestrates the differentiation of Th17 cells, was significantly increased in the intestinal mucosa of patients with aGVHD compared with intestinal mucosa of patients without aGVHD (P=0.01). Since plasmacytoid dendritic cells (PDCs) have been reported to drive the differentiation of the Th17 subset, we quantified PDCs in these patients. PDC CD123+ cells were increased in the intestinal mucosa of patients with aGVHD. Furthermore, the number of CD123+ PDCs paralleled the histological grade of aGVHD, providing evidence for a role of Th17-mediated responses and a potential new pathophysiological link between PDCs and Th17 in human aGVHD.

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
Buy now

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

Figure 1

Similar content being viewed by others

References

  1. Holler E, Kolb HJ, Mittermuller J, Kaul M, Ledderose G, Duell T et al. Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F). Blood 1995; 86: 890–899.

    CAS  PubMed  Google Scholar 

  2. Krenger W, Hill GR, Ferrara JL . Cytokine cascades in acute graft-versus-host disease. Transplantation 1997; 64: 553–558.

    Article  CAS  Google Scholar 

  3. Welniak LA, Blazar BR, Murphy WJ . Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 2007; 25: 139–170.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

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

    Article  CAS  Google Scholar 

  10. 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 

  11. 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 

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

    Article  CAS  Google Scholar 

  13. Sale GE, Shulman HM, McDonald GB, Thomas ED . Gastrointestinal graft-versus-host disease in man. A clinicopathologic study of the rectal biopsy. Am J Surg Pathol 1979; 3: 291–299.

    Article  CAS  Google Scholar 

  14. Epstein RJ, McDonald GB, Sale GE, Shulman HM, Thomas ED . The diagnostic accuracy of the rectal biopsy in acute graft-versus-host disease: a prospective study of thirteen patients. Gastroenterology 1980; 78: 764–771.

    Article  CAS  Google Scholar 

  15. Annunziato F, Cosmi L, Santarlasci V, Maggi L, Liotta F, Mazzinghi B et al. Phenotypic and functional features of human Th17 cells. J Exp Med 2007; 204: 1849–1861.

    Article  CAS  Google Scholar 

  16. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007; 8: 639–646.

    Article  CAS  Google Scholar 

  17. Kleinschek MA, Boniface K, Sadekova S, Grein J, Murphy EE, Turner SP et al. Circulating and gut-resident human Th17 cells express CD161 and promote intestinal inflammation. J Exp Med 2009; 206: 525–534.

    Article  CAS  Google Scholar 

  18. Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006; 126: 1121–1133.

    Article  CAS  Google Scholar 

  19. Swiecki M, Colonna M . Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev 2010; 234: 142–162.

    Article  CAS  Google Scholar 

  20. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007; 449: 564–569.

    Article  CAS  Google Scholar 

  21. Gregorio J, Meller S, Conrad C, Di Nardo A, Homey B, Lauerma A et al. Plasmacytoid dendritic cells sense skin injury and promote wound healing through type I interferons. J Exp Med 2010; 207: 2921–2930.

    Article  CAS  Google Scholar 

  22. Isaksson M, Ardesjo B, Ronnblom L, Kampe O, Lassmann H, Eloranta ML et al. Plasmacytoid DC promote priming of autoimmune Th17 cells and EAE. Eur J Immunol 2009; 39: 2925–2935.

    Article  CAS  Google Scholar 

  23. Yu CF, Peng WM, Oldenburg J, Hoch J, Bieber T, Limmer A et al. Human plasmacytoid dendritic cells support Th17 cell effector function in response to TLR7 ligation. J Immunol 2010; 184: 1159–1167.

    Article  CAS  Google Scholar 

  24. Bonnefoy F, Couturier M, Clauzon A, Remy-Martin JP, Gaugler B, Tiberghien P et al. TGF-beta-exposed plasmacytoid dendritic cells participate in Th17 commitment. J Immunol 2011; 186: 6157–6164.

    Article  CAS  Google Scholar 

  25. Hirota K, Duarte JH, Veldhoen M, Hornsby E, Li Y, Cua DJ et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 2011; 12: 255–263.

    Article  CAS  Google Scholar 

  26. Nistala K, Adams S, Cambrook H, Ursu S, Olivito B, de Jager W et al. Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA 2010; 107: 14751–14756.

    Article  CAS  Google Scholar 

  27. Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY et al. Control of TH17 cells occurs in the small intestine. Nature 2011; 475: 514–518.

    Article  CAS  Google Scholar 

  28. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V et al. Self-RNA-antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med 2009; 206: 1983–1994.

    Article  CAS  Google Scholar 

  29. Guiducci C, Tripodo C, Gong M, Sangaletti S, Colombo MP, Coffman RL et al. Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9. J Exp Med 2010; 207: 2931–2942.

    Article  CAS  Google Scholar 

  30. van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 2009; 182: 5836–5845.

    Article  CAS  Google Scholar 

  31. Mohty M, Blaise D, Faucher C, Vey N, Bouabdallah R, Stoppa AM et al. Inflammatory cytokines and acute graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation. Blood 2005; 106: 4407–4411.

    Article  CAS  Google Scholar 

  32. Platanias LC . Abnormalities in Th17T cells in aplastic anemia. Blood 2010; 116: 4039–4040.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge the technical and logistical support of V Dehame, S Leclercq, S Blandin, C Deleine and E Drouet. We also thank the nursing staff for providing excellent care for our patients, and the following physicians: N Blin, E Brissot, X Cahu, V Dubruille, T Gastinne, JL Harousseau, S Le Gouill, B Mahe, F Mechinaud, P Moreau and F Rialland for their dedicated patient care. We also thank the ‘Région Pays de Loire,’ the ‘Association pour la Recherchesur le Cancer (ARC; Grant #3175 to MM and BG),’ the ‘Fondation de France,’ the ‘Fondation contre la Leucémie,’ the ‘Agence de Biomédecine,’ the ‘Association Cent pour Sang la Vie,’ the ‘Association Laurette Fuguain’ and the IRGHET for their generous and continuous support for our clinical and basic research work. Our transplant program was supported by several grants from the French national cancer institute (PHRC INCa to MM). We acknowledge the continuous support of the cell banking facility (‘tumorotheque’) of the CHU de Nantes.

Author contributions

All authors listed in the manuscript have contributed substantially to this work: conception and design: Mohamad Mohty, Béatrice Gaugler, Céline Bossard and Jean-François Mosnier; financial support: Mohamad Mohty, Béatrice Gaugler, Pierre Tiberghien and Philippe Saas; administrative and logistical support: Mohamad Mohty, Béatrice Gaugler, Pierre Tiberghien and Philippe Saas; provision of study materials and patients care: Patrice Chevallier, Thierry Guillaume, Jacques Delaunay and Mohamad Mohty; experimental work: Céline Bossard, Florent Malard, Jessy Arbez and Béatrice Gaugler; collection and assembly of clinical data: Florent Malard and Mohamad Mohty; data analysis and interpretation: Céline Bossard, Florent Malard, Jessy Arbez, Mohamad Mohty, Béatrice Gaugler, Philippe Saas and Pierre Tiberghien; manuscript writing and revision: Mohamad Mohty, Céline Bossard, Florent Malard and Béatrice Gaugler; final approval of manuscript: all co-authors.

Author information

Author notes

  1. C Bossard and F Malard: These authors contributed equally to this work.

  2. M Mohty and B Gaugler: These authors share senior authorship.

Authors and Affiliations

  1. EA4273 Biometadys, Faculté de Médecine, Université de Nantes, Nantes, France

    C Bossard & J-F Mosnier

  2. Centre Hospitalier et Universitaire (CHU) de Nantes, Laboratoire d'Anatomie et Cytologie Pathologiques, Nantes, France

    C Bossard & J-F Mosnier

  3. INSERM CRNCA UMR892, Nantes, France

    F Malard & M Mohty

  4. Service d'Hématologie Clinique, CHU, Université de Nantes, Nantes, France

    F Malard, P Chevallier, T Guillaume, J Delaunay & M Mohty

  5. INSERM UMR1098, Besançon, France

    J Arbez, P Tiberghien, P Saas & B Gaugler

  6. Université de Franche-Comté, Besançon, France

    J Arbez, P Tiberghien, P Saas & B Gaugler

  7. EFS Bourgogne Franche-Comté, Besançon Cedex, France

    J Arbez, P Tiberghien, P Saas & B Gaugler

  8. Centre d'Investigation Clinique en Biothérapie CBT506, Plateforme de Biomonitoring, Besançon, France

    P Tiberghien, P Saas & B Gaugler

  9. Centre d'Investigation Clinique en Cancérologie (CI2C), Nantes, France

    M Mohty

Authors
  1. C Bossard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F Malard
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Arbez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P Chevallier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Guillaume
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Delaunay
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J-F Mosnier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Tiberghien
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P Saas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M Mohty
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. B Gaugler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M Mohty or B Gaugler.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bossard, C., Malard, F., Arbez, J. et al. Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease. Leukemia 26, 1471–1474 (2012). https://doi.org/10.1038/leu.2012.41

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.41

Keywords

This article is cited by

Search

Advanced search

Quick links