Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity

Cell Communication and Signaling

Research

Debanjana Chatterjee¹  Nicole Marquardt¹  Dejene Milkessa Tufa¹  Hui Zhi Low¹  Roland Jacobs¹  Reinhold Ernst Schmidt¹  Constantin von Kaisenberg²  Tim Hatlapatka³  Cornelia Kasper⁴  Guillaume Beauclair⁵  Ralf Hass⁶ 

[1] Department of Clinical Immunology and Rheumatology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany;Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany;Institute of Technical Chemistry, Leibniz University of Hannover, Hannover, Germany;Institute of Technical Chemistry, Leibniz University of Hannover, Hannover, Germany;Department of Biotechnology, University of Natural Resources and Life Science, Vienna, Austria;Institute of Virology, Hannover Medical School, Hannover, Germany;Laboratory of Biochemistry and Tumor Biology, Clinic of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany;

关键词: UC-MSC;    NK cell cytotoxicity;    Immunosuppression;    IL-1β;    Gamma-secretase;   

DOI  :  10.1186/s12964-014-0063-9

 received in 2014-07-10, accepted in 2014-09-24,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundMesenchymal stem cells (MSCs) are increasingly considered to be used as biological immunosuppressants in hematopoietic stem cell transplantation (HSCT). In the early reconstitution phase following HSCT, natural killer (NK) cells represent the major lymphocyte population in peripheral blood and display graft-vs-leukemia (GvL) effects. The functional interactions between NK cells and MSCs have the potential to influence the leukemia relapse rate after HSCT. Until date, MSC-NK cell interaction studies are largely focussed on bone marrow derived (BM)-MSCs. Umbilical cord derived (UC)-MSCs might be an alternative source of therapeutic MSCs. Thus, we studied the interaction of UC-MSCs with unstimulated allogeneic NK cells.ResultsUC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors. The main soluble immunosuppressant was identified as prostaglandin (PG)-E2. Maximal PGE2 release involved IL-1β priming of MSCs after close contact between the NK cells and UC-MSCs. Interestingly, blocking gamma-secretase activation alleviated the immunosuppression by controlling PGE2 production. IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity.ConclusionAlthough the role of PGE2 in NK cell-MSC has been reported, the requirement of cell-cell contact for PGE2 induced immunosuppression remained unexplained. Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

【 授权许可】

Unknown   
© Chatterjee et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.