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

Valérie Trichet, Cécile Benezech, Christelle Dousset, Marie-Claude Gesnel, Marc Bonneville, Richard Breathnach

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)6129-36
Number of pages8
JournalJournal of Immunology
Volume177
Issue number9
Publication statusPublished - 1 Nov 2006

Keywords

  • Antibodies
  • Cell Line, Tumor
  • Coculture Techniques
  • Cytotoxicity, Immunologic
  • Down-Regulation
  • Histocompatibility Antigens Class I
  • Humans
  • Lymphocyte Activation
  • NK Cell Lectin-Like Receptor Subfamily D
  • NK Cell Lectin-Like Receptor Subfamily K
  • Neoplasms
  • Receptors, Immunologic
  • Receptors, KIR
  • Receptors, Natural Killer Cell
  • T-Lymphocyte Subsets
  • Tumor Escape
  • beta 2-Microglobulin

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