title: Adenovirus Serotype 5 Vaccination Results in Suboptimal CD4 T Helper 1 Responses in Mice.
abstract: Adenovirus serotype 5 (Ad5) is one of the most widely used viral vectors and is known to generate potent T cell responses. While many previous studies have characterized Ad5-induced CD8 T cell responses, there is a relative lack of detailed studies that have analyzed CD4 T cells elicited by Ad5 vaccination. Here, we immunized mice with Ad5 vectors encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) and examined GP-specific CD4 T cell responses elicited by Ad5 vectors and compared them to those induced by an acute LCMV infection. In contrast to LCMV infection, where balanced CD4 T helper 1 (Th1) and T follicular helper (Tfh) responses were induced, Ad5 immunization resulted in a significantly reduced frequency of Th1 cells. CD4 T cells elicited by Ad5 vectors expressed decreased levels of Th1 markers, such as Tim3, SLAM, T-bet, and Ly6C, had smaller amounts of cytotoxic molecules like granzyme B, and produced less interferon gamma than CD4 T cells induced by LCMV infection. This defective CD4 Th1 response appeared to be intrinsic for Ad5 vectors and not a reflection of comparing a nonreplicating vector to a live viral infection, since immunization with a DNA vector expressing LCMV-GP generated efficient CD4 Th1 responses. Analysis at early time points (day 3 or 4) after immunization with Ad5 vectors revealed a defect in the expression of CD25 (interleukin-2 [IL-2] receptor alpha chain) on Ad5-elicited CD4 T cells, and administration of exogenous IL-2 following Ad5 immunization partially restored CD4 Th1 responses. These results suggest that impairment of Th1 commitment after Ad5 immunization could be due to reduced IL-2-mediated signaling.IMPORTANCEDuring viral infection, generating balanced responses of Th1 and Tfh cells is important to induce effective cell-mediated responses and provide optimal help for antibody responses. In this study, to investigate vaccine-induced CD4 T cell responses, we characterized CD4 T cells after immunization with Ad5 vectors expressing LCMV-GP in mice. Ad5 vectors led to altered effector differentiation of LCMV GP-specific CD4 T cells compared to that during LCMV infection. CD4 T cells following Ad5 immunization exhibited impaired Th1 lineage commitment, generating significantly decreased Th1 responses than those induced by LCMV infection. Our results suggest that suboptimal IL-2 signaling possibly plays a role in reduced Th1 development following Ad5 immunization.
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Junghwa
authors.initials: J
authors.lastname: Lee
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Masao
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Im
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Araki
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Hyun-Tak
authors.initials: HT
authors.lastname: Jin
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Carl W
authors.initials: CW
authors.lastname: Davis
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Bogumila T
authors.initials: BT
authors.lastname: Konieczny
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Spies
authors.affiliation: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: M Juliana
authors.initials: MJ
authors.lastname: McElrath
authors.affiliation: Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia, USA rahmed@emory.edu.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
mesh_terms: D000256:Adenoviridae / Q000276:immunology*; D061605:Administration, Intravenous; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D002454:Cell Differentiation / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D007273:Injections, Intramuscular; D008216:Lymphocytic Choriomeningitis / Q000097:blood / Q000276:immunology / Q000517:prevention & control*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology*; D014611:Vaccination; D014764:Viral Proteins / Q000276:immunology; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D006023:Glycoproteins; D014764:Viral Proteins; D014765:Viral Vaccines
keywords: CD4 T cell responses; T follicular helper (Tfh); T helper 1 (Th1); adenovirus serotype 5; vaccination