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

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.