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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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IMMUNOBIOLOGY
Mesenchymal stem cells inhibit natural killer–cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2
Grazia Maria Spaggiari1,2,
Andrea Capobianco1,3,
Heba Abdelrazik4,
Flavio Becchetti4,
Maria Cristina Mingari3,5, and
Lorenzo Moretta1,2,4
1 Centro di Eccellenza per la Ricerca Biomedica,
2 Dipartimento di Medicina Sperimentale, and
3 Dipartimento di Oncologia, Biologia e Genetica, Università di Genova;
4 Istituto Giannina Gaslini, Genova; and
5 Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy
Recently, a number of clinical trials used 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 MSCs and NK cells in HSCT, we have recently explored the result of possible interactions between the 2 cell types. We found that activated NK cells could kill MSCs, whereas MSCs strongly inhibited interleukin-2 (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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