Helper function of memory CD8⁺ T cells: Heterologous CD8 ⁺ T cells support the induction of therapeutic cancer immunity

In contrast to the well-established efficacy of preventive vaccines, the effectiveness of therapeutic vaccines remains limited. To develop effective vaccination regimens against cancer, we have analyzed the effect of effector and memory CD8⁺ T cells on the ability of dendritic cells to mediate the immunologic and antitumor effects of vaccination. We show that in contrast to effector CD8⁺ T cells that kill antigen-carrying dendritic cells, IFNγ-producing memory CD8⁺ T cells act as "helper" cells, supporting the ability of dendritic cells to produce interleukin-12 (IL-12) p70. Promoting the interaction of tumor antigen-carrying dendritic cells with memory-type "heterologous" (tumor-irrelevant) CD8⁺ T cells strongly enhances the IL-12p70-dependent immunogenic and therapeutic effects of vaccination in the animals bearing established tumors. Our data show that the suppressive and helper functions of CD8⁺ T cells are differentially expressed at different phases of CD8⁺ T-cell responses. Selective performance of helper functions by memory (in contrast to effector) CD8⁺ T cells helps to explain the phenomenon of immune memory and facilitates the design of effective therapeutic vaccines against cancer and chronic infections.