TY - JOUR
T1 - Adenovirus serotype 5 vaccine vectors trigger IL-27–dependent inhibitory CD4+ T cell responses that impair CD8+ T cell function
AU - Larocca, Rafael A.
AU - Provine, Nicholas M.
AU - Aid, Malika
AU - Iampietro, M. Justin
AU - Borducchi, Erica N.
AU - Badamchi-Zadeh, Alexander
AU - Abbink, Peter
AU - Ng’ang’a, David
AU - Bricault, Christine A.
AU - Blass, Eryn
AU - Penaloza-MacMaster, Pablo
AU - Stephenson, Kathryn E.
AU - Barouch, Dan H.
N1 - Funding Information:
We thank L. R. Parenteau and S. Blackmore for technical support and the Center for Virology and Vaccine Research Flow Cytometry Core facility for cell sorting. We also thank the NIH Tetramer Core Facility (Emory University) for providing the MHC class I and II monomers used in these studies. We acknowledge support from NIH grants AI060354, AI078526, AI096040 (D.H.B.), AI007245, and AI07387 (P.P.) and Bill & Melinda Gates Foundation grant OPP1033091 (D.H.B.).
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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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U2 - 10.1126/sciimmunol.aaf7643
DO - 10.1126/sciimmunol.aaf7643
M3 - Article
C2 - 28239679
AN - SCOPUS:85041549026
VL - 1
JO - Science immunology
JF - Science immunology
SN - 2470-9468
IS - 5
M1 - eaaf7643
ER -