Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells.
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Authors
Ranjan, SatishGoihl, Alexander
Kohli, Shrey
Gadi, Ihsan
Pierau, Mandy
Shahzad, Khurrum
Gupta, Dheerendra
Bock, Fabian
Wang, Hongjie
Shaikh, Haroon
Kähne, Thilo
Reinhold, Dirk
Bank, Ute
Zenclussen, Ana C
Niemz, Jana
Schnöder, Tina M
Brunner-Weinzierl, Monika
Fischer, Thomas
Kalinski, Thomas
Schraven, Burkhart
Luft, Thomas
Huehn, Jochen
Naumann, Michael
Heidel, Florian H
Isermann, Berend
Issue Date
2017-08-21
Metadata
Show full item recordAbstract
Graft-vs.-host disease (GvHD) is a major complication of allogenic hematopoietic stem-cell(HSC) transplantation. GvHD is associated with loss of endothelial thrombomodulin, but the relevance of this for the adaptive immune response to transplanted HSCs remains unknown. Here we show that the protease-activated protein C (aPC), which is generated by thrombomodulin, ameliorates GvHD aPC restricts allogenic T-cell activation via the protease activated receptor (PAR)2/PAR3 heterodimer on regulatory T-cells (Tregs, CD4(+)FOXP3(+)). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of Tregs and protects from GvHD. Preincubation of human T-cells (HLA-DR4(-)CD4(+)) with aPC prior to transplantation into humanized (NSG-AB°DR4) mice ameliorates graft-vs.-host disease. The protective effect of aPC on GvHD does not compromise the graft vs. leukaemia effect in two independent tumor cell models. Ex vivo preincubation of T-cells with aPC, aPC-based therapies, or targeting PAR2/PAR3 on T-cells may provide a safe and effective approach to mitigate GvHD.Graft-vs.-host disease is a complication of allogenic hematopoietic stem cell transplantation, and is associated with endothelial dysfunction. Here the authors show that activated protein C signals via PAR2/PAR3 to expand Treg cells, mitigating the disease in mice.Citation
Activated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells. 2017, 8 (1):311 Nat CommunAffiliation
Helmholtz Centre for infection research GmbH, Inhoffenstr. 7, 38124 Braunschweig, Germany.Journal
Nature communicationsPubMed ID
28827518Type
ArticleLanguage
enISSN
2041-1723ae974a485f413a2113503eed53cd6c53
10.1038/s41467-017-00169-4
Scopus Count
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- Creative Commons
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/