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Blood, 1 February 2008, Vol. 111, No. 3, pp. 1327-1333.
Prepublished online as a Blood First Edition Paper on October 19, 2007; DOI 10.1182/blood-2007-02-074997.
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Submitted February 21, 2007
Accepted October 10, 2007
Mesenchymal stem cells inhibit natural killer cell proliferation, cytotoxicity and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2
Grazia Maria Spaggiari, Andrea Capobianco, Heba Abdelrazik, Flavio Becchetti, Maria Cristina Mingari, and Lorenzo Moretta*
Centro di Eccellenza per la Ricerca Biomedica, Universita di Genova, Genova, Italy
Dipartimento di Oncologia, Biologia e Genetica, Universita di Genova, Genova, Italy
Istituto Giannina Gaslini, Genova, Italy
Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
Dipartimento di Medicina Sperimentale, Universita di Genova, Genova, Italy
* Corresponding author; email: lorenzomoretta{at}ospedale-gaslini.ge.it.
Recently, a number of clinical trials employed either mesenchymal stem cells (MSCs) or natural killer (NK) cells in an attempt to improve the effectiveness of hematopoietic stem cell transplantation (HSCT). In view of the relevant role of both MSC and NK cells in HSCT, we have recently explored the result of possible interactions between the two cell types. We found that activated NK cells could kill MSCs whereas MSCs strongly inhibited IL-2-induced NK cell proliferation. In this study we further analyzed the inhibitory effect exerted by MSCs on NK cells. We show that MSCs not only inhibit the cytokine-induced proliferation of freshly isolated NK cells but also prevent the induction of effector functions such as cytotoxic activity and cytokine production. Moreover, we show that this inhibitory effect is related to a sharp down-regulation of the surface expression of the activating NK receptors NKp30, NKp44 and NKG2D. Finally, we demonstrate that indoleamine 2,3-dioxygenase and prostaglandin E2 represent key mediators of the MSC-induced inhibition of NK cells.
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