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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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 3

OX40 does not drive CD8+ T cell memory with attenuated viruses or when viral replication is low.

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OX40 does not drive CD8+ T cell memory with attenuated viruses or when v...
(A–G) WT or Ox40–/– mice were infected i.p. with various VACV strains (2 × 105 or 2 × 106 PFU) as indicated. (H) At 1 day after infection with WR, mice were injected i.p. with 200 μg poly:IC. At day 40 (A and B) or day 7 (C, D, F, and G), splenocytes were stained with CD8 plus CD44, CD62L, and B8R or intracellular IFN-γ, and the number of VACV-reactive CD8+ T cells was calculated. (F) Representative plots of gated CD8 cells staining for CD62L and B8R in spleen. Numbers indicate percent CD62L+B8R+ and CD62L–B8R+ cells after gating on CD8+ T cells. Results are mean ± SEM (n = 6 per group). *P < 0.05 vs. WT. Similar results were obtained in 3 separate experiments. (E and H) On day 4 after infection, spleens from the indicated groups were removed from individual mice, and VACV titers were determined as described in Methods. *P < 0.05.