CRTAM Receptor Engagement by Necl-2 on Tumor Cells Triggers Cell Death of Activated Vγ9Vδ2 T Cells

Human V gamma 9V delta 2 T cells exert potent in vitro and in vivo antitumor activities, making them promising candidates for immunotherapy strategies. Recognition of tumor cells by V gamma 9V delta 2 T cells requires engagement of the TCR and/or NK receptors. Recently, one of the novel NK receptors, the class I-restricted T cell-associated molecule (CRTAM), has been described to promote cytotoxic function of NK cells and to lead to IFN-gamma secretion by CD8(+) T cells through interaction with its ligand, Necl-2. A better understanding of the role of CRTAM in V gamma 9V delta 2 T cell functions is highly relevant to optimize innate-like T cell-based cancer immunotherapy. In this article, we report that CRTAM is transiently expressed on activated V gamma 9V delta 2 T lymphocytes following TCR engagement. However, CRTAM-Necl-2 interaction does not modify the cytotoxic function or IFN-gamma secretion of V gamma 9V delta 2 T cells. The expression of CRTAM in activated V gamma 9V delta 2 T cells is quickly downregulated following interaction with Necl-2 on tumor cells. Of interest, CRTAM is concurrently acquired at the cell surface of Necl-2(+) tumor cells through V gamma 9V delta 2 T cell membrane capture. Finally, we highlight that coculture experiments with tumor cells expressing Necl-2 result in significant cell death of CRTAM(+) V gamma 9V delta 2 T cells. CRTAM-mediated cell death is dependent on an autophagic process, but not on apoptosis or necroptosis, as attested by the expression of characteristic markers and blocking experiments with specific inhibitors. On the basis of these findings, we propose that Necl-2 on tumor cells represents a new tumor counterattack mechanism and a potential target to improve efficiency of gamma delta T cell-based immunotherapy. The Journal of Immunology, 2013, 190: 4868-4876.