Identification of HLA-E-Specific Alloreactive T Lymphocytes: A Cell Subset That Undergoes Preferential Expansion in Mixed Lymphocyte Culture and Displays a Broad Cytolytic Activity against Allogeneic Cells

Previous studies showed that a subset of CD8+cytolytic T lymphocytes expressing HLA class I-specific natural killer inhibitory receptors (iNKR) is characterized by the ability to recognize HLA-E and to mediate T cell receptor-dependent killing of different NK cell-susceptible tumor target cells. In this study, we show that this CD8+T cell subset can also undergo extensive proliferation in mixed lymphocyte cultures in response to allogeneic cells. Analysis of their cytolytic activity revealed a broad specificity against a panel of allogeneic phytohemagglutinin-induced blasts derived from HLA-unmatched donors. On the other hand, autologous and certain allogeneic phytohemagglutinin blasts were resistant to lysis. We used as target cells the transporter associated with antigen processing (TAP)-2-/-murine RMA-S cell line cotransfected with β2-microglobulin and HLA-$E^\ast01033$. On loading these cells with different HLA-E-binding peptides derived either from HLA class I leader sequences or viral proteins, we could show that HLA-E-specific cytolytic T lymphocytes recognized many, but not all, peptides analyzed. These data suggest that these cells may recognize, on allogeneic cells, HLA-E with peptides that are not present in the host of origin. In addition to their ability to proliferate in response to allogeneic stimulation and to lyse, most allogeneic cells may have important implications in transplantation and in antitumor immune responses.