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 7

The frequency of CD8+ T cells in the lung prior to challenge directly correlates with the degree of protection against lethal VACV infection.

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The frequency of CD8+ T cells in the lung prior to challenge directly co...
Naive CD8+CD44lo and VACV-reactive memory CD8+CD44hiB8R+ T cells were isolated from WR-infected mice, and varying numbers were instilled into the lungs of naive mice via the trachea. Some groups received 400 μl VACV-immune serum i.p. 1 day after transfer, mice were infected i.n. with a lethal dose of WR (1 × 106 PFU; i.e., 100 × LD50). Animals were weighed daily and euthanized if weight loss was greater than 30% body weight. Mean percent survival (A) and percent of initial body weight (B) are shown. 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. Results are mean (n = 4 per group) from 1 experiment.