title: Adenovirus serotype 5 vaccine vectors trigger IL-27-dependent inhibitory CD4+T cell responses that impair CD8+T cell function.
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 previously been elucidated. Here we demonstrate that, following 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 upregulated expression of IL-10 and PD-1 by CD4+T cells following Ad5 vaccination. These cells markedly suppressed vaccine-elicited CD8+T cell responsesin vivoand IL-10 blockade increased the frequency and functionality of antigen-specific CD8+T cells as well as improved protective efficacy against challenge with recombinantListeria 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.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Larocca
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Provine
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Malika
authors.initials: M
authors.lastname: Aid
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: M Justin
authors.initials: MJ
authors.lastname: Iampietro
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Borducchi
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Badamchi-Zadeh
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Abbink
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ng'ang'a
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Bricault
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Eryn
authors.initials: E
authors.lastname: Blass
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Microbiology and Immunology, Northwestern University, Chicago, IL 66611, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Penaloza-MacMaster
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Stephenson
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch