title: Inhibitory receptor expression on memory CD8 T cells following Ad vector immunization.
abstract: T cells are an important component of immune responses, and their function is influenced by their expression of inhibitory receptors. Immunization with alternative serotype adenovirus (Ad) vectors induces highly functional T cell responses with lower programmed cell death 1 (PD-1) expression and increased boostability relative to Ad5 vectors. However, a detailed phenotypic characterization of other inhibitory receptors is lacking, and it is unknown whether Ad5-induced CD8 T cells eventually recover function with time. In this report, we measure the expression of various inhibitory receptors and memory markers during early and late time points following vaccination with Ad5 and alternative serotype Ad vectors. CD8 T cells induced by Ad5 exhibited increased expression of the inhibitory receptor Tim-3 and showed decreased central memory differentiation as compared with alternative serotype Ad vectors, even a year following immunization. Moreover, relative to Ad5-primed mice, Ad26-primed mice exhibited substantially improved recall of SIV Gag-specific CD8 T cell responses following heterologous boosting with MVA or Ad35 vectors. We also demonstrate that low doses of Ad5 priming resulted in more boostable immune responses with lower PD-1 expression as compared to high Ad5 doses, suggesting a role for vector dose in influencing immune dysfunction following Ad5 vaccination. These data suggest that Ad5 vectors induce a long-term pattern of immune exhaustion that can be partly overcome by lowering vector dose and modulating inhibitory signals.
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
authors: Pablo
authors: P
authors: Penaloza-MacMaster
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
authors: Quazim A
authors: QA
authors: Alayo
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
authors: Joshua
authors: J
authors: Ra
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
authors: Nicholas M
authors: NM
authors: Provine
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
authors: Rafael
authors: R
authors: Larocca
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States.
authors: Benjamin
authors: B
authors: Lee
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States; Ragon Institute of MGH, MIT, and Harvard, Boston, MA 02114, United States. Electronic address: dbarouch@bidmc.harvard.edu.
authors: Dan H
authors: DH
authors: Barouch
mesh_terms: D000256:Adenoviridae; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D005260:Female; D005822:Genetic Vectors; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism; D007114:Immunization; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism
chemical_list: D016207:Cytokines; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: Adenovirus; HIV-1; PD-1; Vector