Up-regulation of cytolytic functions of human Vδ2− γδ T lymphocytes through engagement of ILT2 expressed by tumor target cells

In humans, the majority of peripheral blood gamma delta T cells expresses V gamma 9V delta 2 T-cell receptors (TCR) and recognize nonpeptidic phosphorylated antigens. In contrast, most tissue-derived gamma delta T cells, which are located mainly in spleen and epithelia, preferentially use V delta 1 or V delta 3 chains paired with diverse V gamma chains to form their TCR. Our knowledge about the antigenic specificity and costimulation requirements of human V delta 2(-) gamma delta T cells remains limited. In an attempt to address this important issue, we characterized the specificity of a monoclonal antibody (mAb 256), screened for its ability to specifically inhibit cytolytic responses of several human V delta 2(-) gamma delta T-cell clones against transformed B cells. We show that mAb 256 does not target a TCR ligand but blocks key interactions between non-TCR molecules on effector gamma delta T cells and ILT2 molecule, expressed by tumor targets. In line with the previously reported specificity of this NK receptor for classic and nonclassic major histocompatibility complex (MHC) class I molecules, blockade of MHC class I/ILT2 interactions using MHC class I- or ILT2-specific mAbs and ILT2-Fc molecules inhibited tumor-induced activation of V gamma 8V delta 3 T-cell clones. Therefore, this study describes a new cytotoxic T lymphocyte activation pathway involving MHC class I engagement on gamma delta T cells. (Blood. 2011; 117(10): 2864-2873)