Adenovirus serotype 5 vaccination results in suboptimal CD4 T helper 1 responses in mice

• Type of Material: Article
• Authors: Junghwa Lee, Emory University; Masao Hashimoto, Emory University; Sejin Im, Emory University; Koichi Araki, Emory University; Hyun-Tak Jin, Emory University; Carl Davis, Emory University; Bogumila T. Konieczny, Emory University; Gregory A. Spies, Fred Hutchinson Cancer Research Center; M. Juliana McElrath, Fred Hutchinson Cancer Research Center; Rafi Ahmed, Emory University
• Language: English
• Date: 2017-03-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.01132-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 91
• Issue: 5
• Grant/Funding Information: We acknowledge the NIH Tetramer Core Facility (contract HHSN272201300006C) for provision of MHC class II tetramers.; This work was supported by NIH grants AI030048 to R.A. and AI091493 to R.A. and M.J.M.
• Keywords: CD4 T cell responses; T helper 1 (Th1); Cell Differentiation; Administration, Intravenous; Th1 Cells; Female; Adenoviridae; adenovirus serotype 5; Animals; Glycoproteins; T follicular helper (Tfh); Mice, Inbred C57BL; Viral Vaccines; Injections, Intramuscular; Lymphocytic choriomeningitis virus; Lymphocytic Choriomeningitis; vaccination; Viral Proteins; Antibodies, Viral; Vaccination
• Research Categories: Health Sciences, Immunology; Biology, Microbiology

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 wi th 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.