title: Cross-reactive T cells are involved in rapid clearance of 2009 pandemic H1N1 influenza virus in nonhuman primates.
abstract: In mouse models of influenza, T cells can confer broad protection against multiple viral subtypes when antibodies raised against a single subtype fail to do so. However, the role of T cells in protecting humans against influenza remains unclear. Here we employ a translational nonhuman primate model to show that cross-reactive T cell responses play an important role in early clearance of infection with 2009 pandemic H1N1 influenza virus (H1N1pdm). To "prime" cellular immunity, we first infected 5 rhesus macaques with a seasonal human H1N1 isolate. These animals made detectable cellular and antibody responses against the seasonal H1N1 isolate but had no neutralizing antibodies against H1N1pdm. Four months later, we challenged the 5 "primed" animals and 7 naive controls with H1N1pdm. In naive animals, CD8+ T cells with an activated phenotype (Ki-67+ CD38+) appeared in blood and lung 5-7 days post inoculation (p.i.) with H1N1pdm and reached peak magnitude 7-10 days p.i. In contrast, activated T cells were recruited to the lung as early as 2 days p.i. in "primed" animals, and reached peak frequencies in blood and lung 4-7 days p.i. Interferon (IFN)-γ Elispot and intracellular cytokine staining assays showed that the virus-specific response peaked earlier and reached a higher magnitude in "primed" animals than in naive animals. This response involved both CD4+ and CD8+ T cells. Strikingly, "primed" animals cleared H1N1pdm infection significantly earlier from the upper and lower respiratory tract than the naive animals did, and before the appearance of H1N1pdm-specific neutralizing antibodies. Together, our results suggest that cross-reactive T cell responses can mediate early clearance of an antigenically novel influenza virus in primates. Vaccines capable of inducing such cross-reactive T cells may help protect humans against severe disease caused by newly emerging pandemic influenza viruses.
authors.affiliation: Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Weinfurter
authors.forename: Kevin
authors.initials: K
authors.lastname: Brunner
authors.forename: Saverio V
authors.initials: SV
authors.lastname: Capuano
authors.forename: Chengjun
authors.initials: C
authors.lastname: Li
authors.forename: Karl W
authors.initials: KW
authors.lastname: Broman
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Friedrich
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000097:blood; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D016207:Cytokines / Q000096:biosynthesis; D007114:Immunization / Q000379:methods; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D019394:Ki-67 Antigen / Q000097:blood; D008168:Lung / Q000276:immunology; D008253:Macaca mulatta; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D007252:Influenza Vaccines; D019394:Ki-67 Antigen; D007371:Interferon-gamma; D051997:ADP-ribosyl Cyclase 1
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