HLA class II restricted T-cell receptor gene transfer generates CD4⁺ T cells with helper activity as well as cytotoxic capacity

Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells. In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigen-specific cytolytic activity and the capacity to produce high amounts of cytokines. CD4⁺ and CD8⁺ peripheral-blood-derived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4⁺ T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8⁺ T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4⁺ T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8⁺ T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8⁺ T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4⁺ T cells.