Human gamma delta T cells comprise a first line of defense through T-cell receptor (TCR) recognition of stressed cells. However, the molecular determinants and stress pathways involved in this recognition are largely unknown. Here we show that exposure of tumor cells to various stress situations led to tumor cell recognition by a V.8Vd3 TCR. Using a strategy that we previously developed to identify antigenic ligands of gamma delta TCRs, annexin A2 was identified as the direct ligand of V.8Vd3 TCR, and was found to be expressed on tumor cells upon the stress situations tested in a reactive oxygen species-dependent manner. Moreover, purified annexin A2 was able to stimulate the proliferation of a Vd2neg gamma delta T-cell subset within peripheral blood mononuclear cells and other annexin A2-specific Vd2neg gamma delta T-cell clones could be derived from peripheral blood mononuclear cells. We thus propose membrane exposure of annexin A2 as an oxidative stress signal for some Vd2neg gamma delta T cells that could be involved in an adaptive stress surveillance.