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9V
2 T Cells Revealed by Target Cell 
2-Microglobulin Knockdown1
* Institut National de la Santé et de la Recherche Médicale, Unité 601, Nantes, France; and
Faculté des Sciences, Université de Nantes, Nantes, France
Tumor cells often escape immunosurveillance by down-regulating MHC class I molecule expression. For human V
9V
2 T cells, a major peripheral blood T cell subset with broad antitumor reactivity, this down-regulation can affect signals transmitted by both the inhibitory and the activating MHC class I and Ib-specific NK receptors (NKRs) that these lymphocytes frequently express. To assess the overall impact of MHC down-regulation on V9V2 T cell activation, we used stable 
2-microglobulin knockdown to generate tumor cells with a 
10-fold down-modulation of all MHC class I molecules. This down-modulation had little effect on T cell proliferation or cytokine production, but modified tumor cell killing efficiency. Ab-blocking studies identified ILT2 as an important inhibitor of tumor cell killing by V9V2 T cells. Down-modulation of MHC class I and Ib molecules severely reduced ILT2 inhibitory signaling, but still allowed signaling by activating CD94-based receptors. It also unveiled a frequent enhancing effect of NKG2D on tumor killing by V9V2 T cells. Current models suggest that activating NKRs have less affinity for their MHC ligands than homologous inhibitory NKRs. Our results show that, despite this, activating NKRs recognizing MHC class I molecules play an important role in the increased killing by V9V2 T cells of tumor cells with down-regulated MHC class I molecule expression, and suggest that these T cells will best lyse tumor cells combining MHC class I molecule expression down-regulation with up-regulated NKG2D ligand expression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Association pour la Recherche sur le Cancer, Agence Nationale de la Recherche, European Community FP6 (Cancer Immunotherapy no. 518234) and institutional grants from Institut National de la Santé et de la Recherche Médicale. C.D. is supported by Innate Pharma.
2 V.T. and C.B. contributed equally to this work.
3 Current address: Université de Nantes, EA 3822, Institut National de la Santé et de la Recherche Médicale ERI7, 44035 Nantes, France.
4 Address correspondence and reprint requests to Dr. Marc Bonneville, Institut National de la Santé et de la Recherche Médicale, Unité 601, Institut de Biologie-Centre Hospitalier Régional, 9 Quai Moncousu, 44093 Nantes Cedex 1, France; E-mail address: bonnevil{at}nantes.inserm.fr or Dr. Richard Breathnach, Institut National de la Santé et de la Recherche Médicale, Unité 601, Institut de Biologie-Centre Hospitalier Régional, 9 Quai Moncousu, 44093 Nantes Cedex 1, France; E-mail address: breathna{at}nantes.inserm.fr
5 Abbreviations used in this paper: NKR, NK receptor; aNKR, activating NKR; iNKR, inhibitory NKR; 2m, 2-microglobulin; shRNA, short hairpin RNA; WT, wild-type; KIR, killer Ig-like receptor.
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  A. Thedrez, C. Harly, A. Morice, S. Salot, M. Bonneville, and E. Scotet IL-21-Mediated Potentiation of Antitumor Cytolytic and Proinflammatory Responses of Human V{gamma}9V{delta}2 T Cells for Adoptive Immunotherapy J. Immunol., March 15, 2009; 182(6): 3423 - 3431. [Abstract] [Full Text] [PDF]
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