Abstract NKp80, an activating homodimeric C-type lectin-like receptor (CTLR), is expressed on essentially all human natural killer (NK) cells and stimulates their cytotoxicity and cytokine release. Recently, we demonstrated that the ligand for NKp80 is the myeloid-specific CTLR activation-induced C-type lectin (AICL), which is encoded in the natural killer gene complex (NKC) adjacent to NKp80. Here, we show that NKp80 also is expressed on a minor fraction of human CD8 T cells that exhibit a high responsiveness and an effector memory phenotype. Gene expression profiling and flow cytometric analyses revealed that this NKp80+ T-cell subset is characterized by the coexpression of other NK receptors and increased levels of cytotoxic effector molecules and adhesion molecules mediating access to sites of inflammation. NKp80 ligation augmented CD3-stimulated degranulation and interferon (IFN)γ secretion by effector memory T cells. Furthermore, engagement of NKp80 by AICL-expressing transfectants or macrophages markedly enhanced CD8 T-cell responses in alloreactive settings. Collectively, our data demonstrate that NKp80 is expressed on a highly responsive subset of effector memory CD8 T cells with an inflammatory NK-like phenotype and promotes T-cell responses toward AICL-expressing cells. Hence, NKp80 may enable effector memory CD8 T cells to interact functionally with cells of myeloid origin at sites of inflammation.