Corruption of Dendritic Cell Antigen Presentation During Acute GVHD Leads to Regulatory T-cell Failure and Chronic GVHD

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2016 Jun 25

PMID 27338097

Citations 37

Authors

Lucie Leveque-El Mouttie

Motoko Koyama

Laetitia Le Texier

Kate A Markey

Melody Cheong

Rachel D Kuns

Katie E Lineburg

Bianca E Teal

Kylie A Alexander

Andrew D Clouston

Bruce R Blazar

Geoffrey R Hill

Kelli P A MacDonald

Affiliations

Soon will be listed here.

Abstract

Chronic graft-versus-host disease (cGVHD) is a major cause of late mortality following allogeneic bone marrow transplantation (BMT) and is characterized by tissue fibrosis manifesting as scleroderma and bronchiolitis obliterans. The development of acute GVHD (aGVHD) is a powerful clinical predictor of subsequent cGVHD, suggesting that aGVHD may invoke the immunologic pathways responsible for cGVHD. In preclinical models in which sclerodermatous cGVHD develops after a preceding period of mild aGVHD, we show that antigen presentation within major histocompatibility complex (MHC) class II of donor dendritic cells (DCs) is markedly impaired early after BMT. This is associated with a failure of regulatory T-cell (Treg) homeostasis and cGVHD. Donor DC-restricted deletion of MHC class II phenocopied this Treg deficiency and cGVHD. Moreover, specific depletion of donor Tregs after BMT also induced cGVHD, whereas adoptive transfer of Tregs ameliorated it. These data demonstrate that the defect in Treg homeostasis seen in cGVHD is a causative lesion and is downstream of defective antigen presentation within MHC class II that is induced by aGVHD.

Citing Articles

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References

Xie Y, Wu M, Song R, Ma J, Shi Y, Qin W . A glucocorticoid amplifies IL-2-induced selective expansion of CD4(+)CD25(+)FOXP3(+) regulatory T cells in vivo and suppresses graft-versus-host disease after allogeneic lymphocyte transplantation. Acta Biochim Biophys Sin (Shanghai). 2009; 41(9):781-91. DOI: 10.1093/abbs/gmp067. View

Hippen K, Merkel S, Schirm D, Sieben C, Sumstad D, Kadidlo D . Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med. 2011; 3(83):83ra41. PMC: 3551476. DOI: 10.1126/scitranslmed.3001809. View

MacDonald K, Kuns R, Rowe V, Morris E, Banovic T, Bofinger H . Effector and regulatory T-cell function is differentially regulated by RelB within antigen-presenting cells during GVHD. Blood. 2007; 109(11):5049-57. DOI: 10.1182/blood-2007-01-067249. View

Anasetti C, Logan B, Lee S, Waller E, Weisdorf D, Wingard J . Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012; 367(16):1487-96. PMC: 3816375. DOI: 10.1056/NEJMoa1203517. View

Marcondes A, Karoopongse E, Lesnikova M, Margineantu D, Welte T, Dinarello C . α-1-Antitrypsin (AAT)-modified donor cells suppress GVHD but enhance the GVL effect: a role for mitochondrial bioenergetics. Blood. 2014; 124(18):2881-91. PMC: 4215316. DOI: 10.1182/blood-2014-04-570440. View

Shulman H, Sullivan K, Weiden P, McDonald G, Striker G, Sale G . Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med. 1980; 69(2):204-17. DOI: 10.1016/0002-9343(80)90380-0. View

Chen X, Vodanovic-Jankovic S, Johnson B, Keller M, Komorowski R, Drobyski W . Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood. 2007; 110(10):3804-13. PMC: 2077325. DOI: 10.1182/blood-2007-05-091074. View

Zhang P, Tey S, Koyama M, Kuns R, Olver S, Lineburg K . Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J Immunol. 2013; 191(10):5291-303. DOI: 10.4049/jimmunol.1301181. View

Rieger K, Loddenkemper C, Maul J, Fietz T, Wolff D, Terpe H . Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood. 2005; 107(4):1717-23. DOI: 10.1182/blood-2005-06-2529. View

10.

Sohn S, Kim D, Baek J, Kim J, Lee K, Lee K . Risk-factor analysis for predicting progressive- or quiescent-type chronic graft-versus-host disease in a patient cohort with a history of acute graft-versus-host disease after allogeneic stem cell transplantation. Bone Marrow Transplant. 2006; 37(7):699-708. DOI: 10.1038/sj.bmt.1705313. View

11.

Zhang C, Todorov I, Zhang Z, Liu Y, Kandeel F, Forman S . Donor CD4+ T and B cells in transplants induce chronic graft-versus-host disease with autoimmune manifestations. Blood. 2005; 107(7):2993-3001. DOI: 10.1182/blood-2005-09-3623. View

12.

Radojcic V, Pletneva M, Yen H, Ivcevic S, Panoskaltsis-Mortari A, Gilliam A . STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model. J Immunol. 2009; 184(2):764-74. PMC: 2941975. DOI: 10.4049/jimmunol.0903006. View

13.

Wu T, Young J, Johnston H, Ni X, Deng R, Racine J . Thymic damage, impaired negative selection, and development of chronic graft-versus-host disease caused by donor CD4+ and CD8+ T cells. J Immunol. 2013; 191(1):488-99. PMC: 3746979. DOI: 10.4049/jimmunol.1300657. View

14.

Polansky J, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U . DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008; 38(6):1654-63. DOI: 10.1002/eji.200838105. View

15.

Brunstein C, Miller J, McKenna D, Hippen K, DeFor T, Sumstad D . Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect. Blood. 2015; 127(8):1044-51. PMC: 4768428. DOI: 10.1182/blood-2015-06-653667. View

16.

Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H . mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature. 2013; 499(7459):485-90. PMC: 3759242. DOI: 10.1038/nature12297. View

17.

Robb R, Lineburg K, Kuns R, Wilson Y, Raffelt N, Olver S . Identification and expansion of highly suppressive CD8(+)FoxP3(+) regulatory T cells after experimental allogeneic bone marrow transplantation. Blood. 2012; 119(24):5898-908. DOI: 10.1182/blood-2011-12-396119. View

18.

Taylor P, Lees C, Blazar B . The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood. 2002; 99(10):3493-9. DOI: 10.1182/blood.v99.10.3493. View

19.

Koreth J, Matsuoka K, Kim H, McDonough S, Bindra B, Alyea 3rd E . Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011; 365(22):2055-66. PMC: 3727432. DOI: 10.1056/NEJMoa1108188. View

20.

Zhao D, Young J, Chen Y, Shen E, Yi T, Todorov I . Alloimmune response results in expansion of autoreactive donor CD4+ T cells in transplants that can mediate chronic graft-versus-host disease. J Immunol. 2010; 186(2):856-68. PMC: 3891909. DOI: 10.4049/jimmunol.1002195. View