Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD

Leveque-El Mouttie, Lucie, Koyama, Motoko, Le Texier, Laetitia, Markey, Kate A., Cheong, Melody, Kuns, Rachel D., Lineburg, Katie E., Teal, Bianca E., Alexander, Kylie A., Clouston, Andrew D., Blazar, Bruce R., Hill, Geoffrey R. and MacDonald, Kelli P. A. (2016) Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD. Blood, 128 6: 794-804. doi:10.1182/blood-2015-11-680876


Author Leveque-El Mouttie, Lucie
Koyama, Motoko
Le Texier, Laetitia
Markey, Kate A.
Cheong, Melody
Kuns, Rachel D.
Lineburg, Katie E.
Teal, Bianca E.
Alexander, Kylie A.
Clouston, Andrew D.
Blazar, Bruce R.
Hill, Geoffrey R.
MacDonald, Kelli P. A.
Title Corruption of dendritic cell antigen presentation during acute GVHD leads to regulatory T-cell failure and chronic GVHD
Journal name Blood   Check publisher's open access policy
ISSN 0006-4971
1528-0020
Publication date 2016-08-11
Year available 2016
Sub-type Article (original research)
DOI 10.1182/blood-2015-11-680876
Open Access Status Not yet assessed
Volume 128
Issue 6
Start page 794
End page 804
Total pages 11
Place of publication Washington, DC, United States
Publisher American Society of Hematology
Language eng
Subject 1303 Biochemistry
2403 Immunology
2720 Hematology
1307 Cell Biology
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.
Keyword Hematology
Hematology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1031728
R01 HL11879
P01 AI-56299
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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