CD70 and IFN-1 selectively induce eomesodermin or T-bet and synergize to promote CD8+ T-cell responses

CD70-mediated stimulation of CD27 is an important cofactor of CD4+ T-cell licensed dendritic cells (DCs). However, it is unclear how CD70-mediated stimulation of T cells is integrated with signals that emanate from signal 3 pathways, such as type-1 interferon (IFN-1) and IL-12. We find that while stimulation of CD27 in isolation drives weak EomesoderminhiT-betlo CD8+ T-cell responses to OVA immunization, profound synergistic expansion is achieved by cotargeting TLR. This cooperativity can substantially boost antiviral CD8+ T-cell responses during acute infection. Concomitant stimulation of TLR significantly increases per cell IFN-? production and the proportion of the population with characteristics of short-lived effector cells, yet also promotes the ability to form long-lived memory. Notably, while IFN-1 contributes to the expression of CD70 on DCs, the synergy between CD27 and TLR stimulation is dependent upon IFN-1's effect directly on CD8+ T cells, and is associated with the increased expression of T-bet in T cells. Surprisingly, we find that IL-12 fails to synergize with CD27 stimulation to promote CD8+ T-cell expansion, despite its capacity to drive effector CD8+ T-cell differentiation. Together, these data identify complex interactions between signal 3 and costimulatory pathways, and identify opportunities to influence the differentiation of CD8+ T-cell responses

Promises and limitations of murine models in the development of anticancer T-cell vaccines

Murine models have been instrumental in defining the basic mechanisms of antitumor immunity. Most of these mechanisms have since been shown to operate in humans as well. Based on these similarities, active vaccination strategies aimed at eliciting antitumor T-cell responses have been elaborated and successfully implemented in various mouse models. However, the results of human antitumor vaccination trials have been rather disappointing thus far. This review summarizes the different experimental approaches used in mice to induce antitumor T-cell responses and identifies some critical parameters that should be considered when evaluating results from murine models