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 Eomesodermin(hi) T-bet(lo) 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-γ production and the proportion of the population with characte... More
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 Eomesodermin(hi) T-bet(lo) 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-γ 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.
