NK-CTLs, a novel HLA-E-restricted T-cell subset

Natural-killer-cytotoxic T lymphocytes (NK-CTLs) are a subset of CD8+ CTLs that express HLA (human leukocyte antigen) class I-specific inhibitory receptors. They are detectable in the blood of some individuals as monoclonal expansions and, similar to NK cells, are capable of killing various tumor cell lines. Here, we discuss recent advances that enabled the unraveling of the molecular mechanism by which these cells kill tumors. NK-CTLs, through their T-cell receptor (TCR), recognize HLA-E, a non classical HLA class I molecule characterized by a limited polymorphism and by the ability to bind peptides derived from the leader sequence of various HLA class I alleles as well as from several viral proteins. In addition, NK-CTLs display a broad alloreactivity but spare self cells. In vivo, they are probably generated on recognition of HLA-E-associated viral peptides, undergoing subsequent clonal expansion. Although NK-CTLs might have a role in antiviral defenses, their broad ability to recognize and kill allogeneic cells might pose serious problems in transplantation.