The current data show that, in contrast to effector CD8+
T cells that kill dendritic cells and suppress antigen-specific immune responses (13
), memory CD8+
T cells can act as de facto helper cells, supporting the dendritic cell–mediated immunologic and antitumor effects of cancer vaccines.
Our observations that OVA257–264
T-cell responses can both benefit from the “helper signals” delivered by memory cells (e.g., from LCMV-specific CD8+
T cells) and provide such signals directly show that CD8+
T cells of a single specificity can first benefit from the help delivered by memory T cells and, once expanded and having reached memory stage, they can themselves act as helper cells. The ability of memory CD8+
T cells to support the dendritic cell–mediated activation of additional naïve CD8+
T cells suggests that the phenomenon of immune memory, in addition to qualitative changes in the activation requirements of memory cells (5
), may also involve a different pattern of interaction of CD8+
T cells with antigen-carrying dendritic cells.
Our findings help to explain the requirement for a delayed administration of booster doses of preventive vaccines to achieve the optimal expansion of pathogen-specific CD8+
T cells and the optimal vaccine effectiveness (9
). Interestingly, recent evidence indicates that priming done under noninflammatory conditions allows for effective administration of booster vaccines substantially sooner than when priming with live pathogen (9
). However, it remains to be tested whether such noninflammatory priming conditions result in impaired induction of the effector (and thus suppressive) functions of the pathogen-specific CD8+
The existence of distinct suppressor and helper stages of CD8+
T-cell activation may help to explain the generally poor efficacy of therapeutic vaccinations of cancer-bearing patients that show predominance of terminally differentiated effector cells (31
). It also helps to explain the high efficacy of prime-boosting vaccination strategies (8
) when the first and second doses of vaccine are delivered using antigenically distinct vectors.
The mechanism of helper function of memory CD8+
T cells in the settings of established cancer is a subject of our current follow-up analyses. Whereas our data show the key role of antigen-carrying dendritic cells in this respect, it is unclear whether the heterologous memory CD8+
T cells just hyperactivate dendritic cells, allowing them to provide immunostimulatory signals to naïve/resting tumor-specific CD8+
T cells before their destruction by effector cells, or memory CD8+
T cells can also protect antigen-carrying dendritic cells from CTL killing. It has been recently proposed that the CD4+
T-cell help for CTL responses is essential mainly for the secondary expansion of CD8+
T cells rather than for their effective priming (10
). These observations raise the possibility that the protection of dendritic cells from CTL killing (21
) may be as important as the originally proposed dendritic cell activation or “licensing” (35
) in the overall mechanism of the CD4+
The current data directly implicate the possibility of enhancing the effectiveness of therapeutic vaccination of cancer patients by incorporating tumor-unrelated heterologous epitopes that promote the interaction of the vaccine-carrying antigen-presenting cells with naturally occurring or artificially induced memory-type T cells. Whereas in the current studies we either have used (in vitro) high numbers of resting CD8+ T cells from TCR-transgenic animals or have involved (in vivo) the memory CD8+ T cells induced by a preimmunization of wild-type animals, the most obvious source of heterologous CD8 help in cancer patients are the memory-type CD8+ T cells induced naturally by past infections or prior vaccinations against “childhood diseases” or such pathogens as influenza or hepatitis.
Our data showing that the helper functions are a selective feature of memory CD8+ T cells, but not effector cells, indicate the existence of a novel mechanism contributing to the phenomenon of CD8+ T-cell memory. Our observations help to explain the benefits of delayed application of booster doses of preventive vaccines and the high efficacy of prime-boost vaccination strategies, facilitating the development of effective strategies of therapeutic vaccination of patients with cancer and chronic infections.