title: CD70 and IFN-1 selectively induce eomesodermin or T-bet and synergize to promote CD8+ T-cell responses.
abstract: 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.
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Dong
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Franklin
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Shane B
authors.initials: SB
authors.lastname: Ritchea
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Cancer Sciences Division, Southampton University School of Medicine, General Hospital, Southampton, UK.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.affiliation: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Timothy N J
authors.initials: TN
authors.lastname: Bullock
mesh_terms: D000818:Animals; D053282:CD27 Ligand / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007156:Immunologic Memory; D007370:Interferon Type I / Q000494:pharmacology*; D018664:Interleukin-12 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020825:T-Box Domain Proteins / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: D053282:CD27 Ligand; C491198:Eomes protein, mouse; D007370:Interferon Type I; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D051193:Toll-Like Receptors; D018664:Interleukin-12
keywords: CD27; CD70; CD8+ T cells; IFN-1; IL-12