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

Rafael A. Larocca, Nicholas M. Provine, Malika Aid, M. Justin Iampietro, Erica N. Borducchi, Alexander Badamchi-Zadeh, Peter Abbink, David Ng’ang’a, Christine A. Bricault, Eryn Blass, Pablo Penaloza-MacMaster, Kathryn E. Stephenson, Dan H. Barouch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbereaaf7643
JournalScience Immunology
Volume1
Issue number5
DOIs
StatePublished - 2016

ASJC Scopus subject areas

  • Immunology and Allergy

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