The TNFR family members OX40 and CD27 link viral virulence to protective T cell vaccines in mice
Shahram Salek-Ardakani, … , Stephen P. Schoenberger, Michael Croft
Shahram Salek-Ardakani, … , Stephen P. Schoenberger, Michael Croft
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):296-307. https://doi.org/10.1172/JCI42056.
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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 9

WR and Lister scarification generates superior protective CD8+ T cell immunity against i.n. viral challenge that is mediated by CD28, OX40, and CD27.

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WR and Lister scarification generates superior protective CD8+ T cell im...
WT mice were infected by dermal scarification with WR and Lister (2 × 105 PFU). (A) On the indicated days after infection, VACV titers at the site of infection were determined as described in Methods. *P < 0.05. (B–D) 8 days after infection, splenocytes were harvested and stained with anti-CD8, -CD44, and -B8R or for intracellular IFN-γ after restimulation with B8R peptide. (B and C) Representative plots of gated CD8 cells staining for CD44 and B8R in spleen. Numbers indicate percent CD44+B8R+ cells after gating on CD8+ T cells. Total number of CD8+CD44+B8R+ T cells per organ was determined as described in Methods. (D) Percent CD8+IFN-γ+ T cells per spleen specific for B8R peptide. Results are mean ± SEM (n = 4 per group) from 1 of 3 experiments. *P < 0.05. (E) MHCII–/– mice were immunized by dermal scarification with WR and Lister (2 × 105 PFU). 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 30% body weight. Mean weight data in some cases were not plotted beyond the point at which mice died and beyond day 7 reflected only mice that survived infection.