Complex interplay of activating and inhibitory signals received by Vgamma9Vdelta2 T cells revealed by target cell beta2-microglobulin knockdown.
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.
Trichet
Valérie
V
Institut National de la Santé et de la Recherche Médicale, Unité 601, Nantes, France.
Benezech
Cécile
C
Dousset
Christelle
C
Gesnel
Marie-Claude
MC
Bonneville
Marc
M
Breathnach
Richard
R
D000906:Antibodies / Q000494:pharmacology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D015536:Down-Regulation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D051920:NK Cell Lectin-Like Receptor Subfamily D / Q000378:metabolism; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009369:Neoplasms / Q000276:immunology*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019139:Tumor Escape; D001613:beta 2-Microglobulin / Q000037:antagonists & inhibitors* / Q000235:genetics
D000906:Antibodies; D015395:Histocompatibility Antigens Class I; C497869:KLRD1 protein, human; C527085:KLRK1 protein, human; D051920:NK Cell Lectin-Like Receptor Subfamily D; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D001613:beta 2-Microglobulin