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 2

VACV virulence correlates with magnitude of CD8+ T cell memory.

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VACV virulence correlates with magnitude of CD8+ T cell memory. WT m...
WT mice were infected i.p. (A and C–F) or i.n. (B) with the indicated VACV strains. Splenocytes and lung cells were harvested on day 40 (A), day 60 (B), day 540 (C and D), or days 4, 5, 6, 7, and 8 (E and F) after infection and stained with anti-CD8, -CD44, and -B8R or for intracellular IFN-γ after restimulation with the designated VACV peptides. (A) Representative plots of gated CD8+ T cells staining for CD44 and B8R in spleen and lung. Numbers indicate percent CD44+B8R+ cells after gating on CD8+ T cells. Total numbers of CD8+CD44+B8R+ T cells per organ were determined as described in Methods. *P < 0.05 vs. WR. (B) Number of CD8+IFN-γ+ T cells per lung specific for peptides B8R, A3L, A8R, and B2R. (C and D) Percent CD8+IFN-γ+ T cells per spleen (C) or lung (D) specific for B8R and A8R. (E and F) Total number of CD8+CD44+B8R+ (E) and CD8+IFN-γ+ (F) T cells per spleen at the indicated time points after infection with VACV variants. Results are mean ± SEM (n = 4 per group) from 1 of 2 experiments. *P < 0.05 vs. all other strains or as otherwise denoted.