The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice
Shahram Salek-Ardakani, Rachel Flynn, Ramon Arens, Hideo Yagita, Geoffrey L. Smith, Jannie Borst, Stephen P. Schoenberger, Michael Croft
Shahram Salek-Ardakani, Rachel Flynn, Ramon Arens, Hideo Yagita, Geoffrey L. Smith, Jannie Borst, Stephen P. Schoenberger, Michael Croft
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Research Article

The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice

Abstract

Induction of CD8+ T cell immunity is a key characteristic of an effective vaccine. For safety reasons, human vaccination strategies largely use attenuated nonreplicating or weakly replicating poxvirus-based vectors, but these often elicit poor CD8+ T cell immunity and might not result in optimal protection. Recent studies have suggested that virulence is directly linked to immunogenicity, but the molecular mechanisms underlying optimal CD8+ T cell responses remain to be defined. Here, using natural and recombinant vaccinia virus (VACV) strains, we have shown in mice that VACV strains of differing virulence induce distinct levels of T cell memory because of the differential use of TNF receptor (TNFR) family costimulatory receptors. With strongly replicating (i.e., virulent) VACV, the TNFR family costimulatory receptors OX40 (also known as CD134) and CD27 were engaged and promoted the generation of high numbers of memory CD8+ T cells, which protected against a lethal virus challenge in the absence of other mechanisms, including antibody and help from CD4+ T cells. In contrast, weakly replicating (i.e., low-virulence) VACV strains were poor at eliciting protective CD8+ T cell memory, as only the Ig family costimulatory receptor CD28 was engaged, and not OX40 or CD27. Our results suggest that the virulence of a virus dictates costimulatory receptor usage to determine the level of protective CD8+ T cell immunity.

Authors

Shahram Salek-Ardakani, Rachel Flynn, Ramon Arens, Hideo Yagita, Geoffrey L. Smith, Jannie Borst, Stephen P. Schoenberger, Michael Croft

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Figure 8

Enhanced CD8+ T cell responses to attenuated VACVs following agonist anti-OX40 treatment.

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Enhanced CD8+ T cell responses to attenuated VACVs following agonist ant...
WT (A and B) and MHCII–/– (C–E) mice were infected with 2 × 105 PFU Lister i.p. 1 day later, mice were treated with 150 μg control rat IgG or anti-OX40 (αOX40). 8 days after infection, VACV-specific CD8+ T cells were assessed by tetramer (A and C) or by intracellular IFN-γ staining after stimulation with the indicated VACV peptides (B and D). Data are either representative plots of tetramer staining in gated CD8+ T cells, with percent positive indicated, or total number (mean ± SEM) of CD8+IFN-γ+ T cells per spleen from 4 individual mice. *P < 0.05. Similar results were obtained in 2 separate experiments. (E) MHCII–/– mice were immunized i.p. with WR or Lister (2 × 105 PFU). 1 day later, cohorts of Lister-immunized mice were treated with 150 μg anti-OX40. Naive MHCII–/– mice were used as control. 10 weeks after vaccination, mice were infected i.n. with a lethal dose of WR (4.5 × 106 PFU; i.e., 400 × LD50). Animals were weighed daily and euthanized if weight loss was greater than 25% body weight. Mean percent of initial body weight is shown, with percent survival indicated.