Open AccessActivated protein C protects from GvHD via PAR2/PAR3 signalling in regulatory T-cells
Author(s) -
Satish Ranjan,
Alexander Goihl,
Shruti Kohli,
Ihsan Gadi,
Mandy Pierau,
Khurrum Shahzad,
Dheerendra Gupta,
Fabian Bock,
Hongjie Wang,
Haroon Shaikh,
Thilo Kähne,
Dirk Reinhold,
Ute Bank,
Ana Claudia Zenclussen,
Jaiemz,
Tina M. Schnöder,
Monika C. BrunnerWeinzierl,
Thomas Fischer,
Thomas Kalinski,
Burkhart Schraven,
Thomas Luft,
Jochen Huehn,
Michael Naumann,
Florian H. Heidel,
Berend Isermann
Publication year - 2017
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-017-00169-4
Subject(s) - foxp3 , thrombomodulin , immunology , graft versus host disease , stem cell , transplantation , hematopoietic stem cell transplantation , haematopoiesis , cancer research , regulatory t cell , medicine , downregulation and upregulation , t cell , immune system , biology , il 2 receptor , microbiology and biotechnology , thrombin , platelet , biochemistry , gene
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 (T regs , CD4 + FOXP3 + ). Preincubation of pan T-cells with aPC prior to transplantation increases the frequency of T regs 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.