Abstract
IL-35 is a newly discovered inhibitory cytokine secreted by regulatory T cells (Tregs) and may have therapeutic potential in several inflammatory disorders. Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation and caused by donor T cells and inflammatory cytokines. The role of IL-35 in aGVHD is still unknown. Here we demonstrate that IL-35 overexpression suppresses CD4+ effector T-cell activation, leading to a reduction in alloreactive T-cell responses and aGVHD severity. It also leads to the expansion of CD4+Foxp3+ Tregs in the aGVHD target organs. Furthermore, IL-35 overexpression results in a selective decrease in the frequency of Th1 cells and an increase of IL-10-producing CD4+ T cells in aGVHD target tissues. Serum levels of TNF-α, IFN-γ, IL-6, IL-22 and IL-23 decrease and IL-10 increases in response to IL-35. Most importantly, IL-35 preserves graft-versus-leukemia effect. Finally, aGVHD grade 2–4 patients have decreased serum IL-35 levels comparing with time-matched patients with aGVHD grade 0–1. Our findings indicate that IL-35 has an important role in reducing aGVHD through promoting the expansion of Tregs and repressing Th1 responses, and should be investigated as the therapeutic strategy for aGVHD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Blazar BR, Murphy WJ . Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD). Philos Trans R Soc Lond B Biol Sci 2005; 360: 1747–1767.
Ferrara JL, Reddy P . Pathophysiology of graft-versus-host disease. Semin Hematol 2006; 43: 3–10.
Shlomchik WD . Graft-versus-host disease. Nat Rev Immunol 2007; 7: 340–352.
Bluestone JA, Abbas AK . Natural versus adaptive regulatory T cells. Nat Rev Immunol 2003; 3: 253–257.
Jiang H, Chess L . An integrated view of suppressor T cell subsets in immunoregulation. J Clin Invest 2004; 114: 1198–1208.
Shevach EM . From vanilla to 28 flavors: multiple varieties of T regulatory cells. Immunity 2006; 25: 195–201.
Taylor PA, Noelle RJ, Blazar BR . CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med 2001; 193: 1311–1318.
Sakaguchi S . Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345–352.
Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL . CD4(+)CD25(+) immuno- regulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med 2002; 196: 401–406.
Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S . Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002; 196: 389–399.
Johnson BD, Konkol MC, Truitt RL . CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant 2002; 8: 525–535.
Taylor PA, Lees CJ, Blazar BR . The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002; 99: 3493–3499.
Paczesny S, Hanauer D, Sun Y, Reddy P . New perspectives on the biology of acute GVHD. Bone Marrow Transplant 2010; 45: 1–11.
Devergne O, Birkenbach M, Kieff E . Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12 form a novel heterodimeric hematopoietin. Proc Natl Acad Sci USA 1997; 94: 12041–12046.
Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007; 450: 566–569.
Collison LW, Pillai MR, Chaturvedi V, Vignali DA . Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol 2009; 182: 6121–6128.
Olson BM, Jankowska-Gan E, Becker JT, Vignali DA, Burlingham WJ, McNeel DG . Human prostate tumor antigen-specific CD8+ regulatory T cells are inhibited by CTLA-4 or IL-35 blockade. J Immunol 2012; 189: 5590–5601.
Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature 2014; 507: 366–370.
Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 2010; 11: 1093–1101.
Kochetkova I, Golden S, Holderness K, Callis G, Pascual DW . IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. J Immunol 2010; 184: 7144–7153.
Niedbala W, Wei XQ, Cai B, Hueber AJ, Leung BP, McInnes IB et al. IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 2007; 37: 3021–3029.
Cooke KR1, Kobzik L, Martin TR, Brewer J, Delmonte J Jr, Crawford JM et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 1996; 88: 3230–3239.
Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL . Total body irra-diation and acute graft-versus-host disease: the role of gastrointestinal damageand inflammatory cytokines. Blood 1997; 90: 3204–3213.
Cooke KR1, 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.
Zakrzewski JL, Kochman AA, Lu SX, Terwey TH, Kim TD, Hubbard VM et al. Adoptive transfer of T-cell precursors enhances T-cell reconstitution after allogeneic hematopoietic stem cell transplantation. Nat Med 2006; 12: 1039–1047.
Beres AJ, Haribhai D, Chadwick AC, Gonyo PJ, Williams CB, Drobyski WR . CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity. J Immunol 2012; 189: 464–474.
Robb RJ, Lineburg KE, Kuns RD, Wilson YA, Raffelt NC, Olver SD et al. Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood 2012; 119: 5898–5908.
Weston LE, Geczy AF, Briscoe H . Production of IL-10 by alloreactive sibling donor cells and its influence on the development of acute GVHD. Bone Marrow Transplant 2006; 37: 207–212.
Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011; 34: 566–578.
Huber S, Gagliani N, Esplugues E, O'Connor W Jr, Huber FJ, Chaudhry A et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3(-) and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 2011; 34: 554–565.
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.
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.
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.
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.
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.
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.
Bahr F, Wehner R, Platzbecker U, Wermke M, Shayegi N, Middeke JM et al. Reconstitution of interleukin-17-producing T helper cells after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2013; 19: 357–365.
Bossard C, Malard F, Arbez J, Chevallier P, Guillaume T, Delaunay J et al. Plasmacytoid dendritic cells and Th17 immune response contribution in gastrointestinal acute graft-versus-host disease. Leukemia 2012; 26: 1471–1474.
Malard F, Bossard C, Brissot E, Chevallier P, Guillaume T, Delaunay J et al. Increased plasmacytoid dendritic cells and RORγt-expressing immune effectors in cutaneous acute graft-versus-host disease. J Leukoc Biol 2013; 94: 1337–1343.
Van den Brink MR, Burakoff SJ . Cytolytic pathways in haematopoietic stem-cell transplantation. Nat Rev Immunol 2002; 2: 273–281.
Acknowledgements
We thank Karen Forbes and Creg Workman for generating and purifying the anti-Ebi3 mAb. This work has been supported by the grants from National Natural Science Foundation of China (91029703, 81102271 and 81273268), the project funding from Suzhou city (SS201032, SZS201109), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), Jiangsu Province’s Key Medical Center (ZX201102), 2012 Jiangsu Provincial Special Program of Medical Science (BL2012005), National clinical key subject construction project, National Public Health Grand Research Foundation (201202017), Jiangsu Provincial Innovative Research Team, Qing Lan project of Jiangsu Province, Program for Changjiang Scholars and Innovative Research Team in University (IRT1075). DAAV was supported by the National Institutes of Health (R01 AI091977), NCI Comprehensive Cancer Center Support CORE grant (CA21765) and ALSAC.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
DAAV has submitted patents around IL-35 that are pending and is entitled to a share in net income generated from licensing of these patent rights for commercial development. The remaining authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Liu, Y., Wu, Y., Wang, Y. et al. IL-35 mitigates murine acute graft-versus-host disease with retention of graft-versus-leukemia effects. Leukemia 29, 939–946 (2015). https://doi.org/10.1038/leu.2014.310
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/leu.2014.310
This article is cited by
-
IL-39 promotes chronic graft-versus-host disease by increasing T and B Cell pathogenicity
Experimental Hematology & Oncology (2022)
-
Dendritic cell-derived IL-27 p28 regulates T cell program in pathogenicity and alleviates acute graft-versus-host disease
Signal Transduction and Targeted Therapy (2022)
-
PD-L1 Ameliorates Murine Acute Graft-Versus-Host Disease by Suppressing Effector But Not Regulatory T Cells Function
Archivum Immunologiae et Therapiae Experimentalis (2019)
-
IL-35 Pretreatment Alleviates Lipopolysaccharide-Induced Acute Kidney Injury in Mice by Inhibiting NF-κB Activation
Inflammation (2017)
-
Interleukin-35 administration counteracts established murine type 1 diabetes – possible involvement of regulatory T cells
Scientific Reports (2015)