Research ArticleVACCINES

Adenovirus serotype 5 vaccine vectors trigger IL-27–dependent inhibitory CD4+ T cell responses that impair CD8+ T cell function

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Science Immunology  04 Nov 2016:
Vol. 1, Issue 5, eaaf7643
DOI: 10.1126/sciimmunol.aaf7643

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Rejuvenating viral vectors

Adenovirus serotype 5 (Ad5) vaccine vectors elicit mixed responses—they induce protective CD8+ T cells, but these cells may be partially exhausted. Now, Larocca et al. demonstrate that this exhausted phenotype may result from Ad5 vector–induced antigen-specific CD4+ T cells that express interleukin-10 (IL-10) and programmed cell death 1 (PD-1) in both mice and macaques. These IL-10+CD4+ T cells suppress the vaccine-induced CD8+ T cell response, and their inhibitory function may depend in part on IL-27. These data suggest that targeting this inhibitory pathway may enhance protection of viral vector–based vaccines.


Adenovirus serotype 5 (Ad5) vaccine vectors elicit robust CD8+ T cell responses, but these responses typically exhibit a partially exhausted phenotype. However, the immunologic mechanism by which Ad5 vectors induce dysfunctional CD8+ T cells has not been elucidated previously. Here, we demonstrate that, after immunization of B6 mice, Ad5 vectors elicit antigen-specific IL-10+CD4+ T cells with a distinct transcriptional profile in a dose-dependent fashion. In rhesus monkeys, we similarly observed up-regulated expression of interleukin-10 (IL-10) and programmed cell death 1 (PD-1) by CD4+ T cells after Ad5 vaccination. These cells markedly suppressed vaccine-elicited CD8+ T cell responses in mice, and IL-10 blockade increased the frequency and functionality of antigen-specific CD8+ T cells, as well as improved protective efficacy against challenge with recombinant Listeria monocytogenes. Moreover, induction of these inhibitory IL-10+CD4+ T cells correlated with IL-27 expression, and IL-27 blockade substantially improved CD4+ T cell functionality. These data highlight a role for IL-27 in the induction of inhibitory IL-10+CD4+ T cells, which suppress CD8+ T cell magnitude and function following Ad5 vector immunization. A deeper understanding of the cytokine networks and transcriptional profiles induced by vaccine vectors should lead to strategies to improve the immunogenicity and protective efficacy of viral vector–based vaccines.

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