Complex interplay of activating and inhibitory signals received by Vgamma9Vdelta2 T cells revealed by target cell beta2-microglobulin knockdown

• Published in: The Journal of immunology (1950) 2006-11, Vol.177 (9), p.6129-6136
• Main Authors: Trichet, Valérie, Benezech, Cécile, Dousset, Christelle, Gesnel, Marie-Claude, Bonneville, Marc, Breathnach, Richard
• Format: Article
• Language: English
• Subjects: Antibodies - pharmacology; beta 2-Microglobulin - antagonists & inhibitors; beta 2-Microglobulin - genetics; Cell Line, Tumor; Coculture Techniques; Cytotoxicity, Immunologic - genetics; Down-Regulation; Histocompatibility Antigens Class I - metabolism; Humans; Lymphocyte Activation; Neoplasms - immunology; NK Cell Lectin-Like Receptor Subfamily D - metabolism; NK Cell Lectin-Like Receptor Subfamily K; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - metabolism; Receptors, KIR; Receptors, Natural Killer Cell; T-Lymphocyte Subsets - immunology; Tumor Escape
• ISSN: 0022-1767

Tumor cells often escape immunosurveillance by down-regulating MHC class I molecule expression. For human Vgamma9Vdelta2 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 Vgamma9Vdelta2 T cell activation, we used stable beta(2)-microglobulin knockdown to generate tumor cells with a approximately 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 Vgamma9Vdelta2 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 Vgamma9Vdelta2 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 Vgamma9Vdelta2 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.