Intranasal Introduction of Fc-Fused Interleukin-7 Provides Long-Lasting Prophylaxis against Lethal Influenza Virus Infection

Abstract

Influenza IMPORTANCEThe major consequence of a highly pathogenic IAV infection is severe pulmonary inflammation, which can result in organ failure and death at worst. Although vaccines for seasonal IAVs are effective, frequent variation of surface viral proteins hampers development of protective immunity. In this study, we demonstrated that intranasal IL-7-mFc pretreatment protected immunologically naive mice from lethal IAV infections. Intranasal pretreatment with IL-7-mFc induced an infiltration of T cells in the lung, which reside as effector/memory T cells with lung-retentive markers. Those IL-7-primed pulmonary T cells contributed to development of protective immunity upon IAV infection, reducing pulmonary immunopathology while increasing IAV-specific cytotoxic T lymphocytes. Since a single treatment with IL-7-mFc was effective in the protection against multiple strains of IAV for an extended period of time, our findings suggest a possibility that IL-7-mFc treatment, as a potential prophylaxis, can be developed for controlling highly pathogenic IAV infections.

Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

“…In our previous study, we found that Fc-fused IL7 could alter pulmonary immune environment after intranasal treatment (35). In addition, this study showed that FcRn in the lung was indispensable for transcytosis and immunomodulation of IL7-Fc, which is consistent with this study's results of immunomodulatory activity in the genital tract.…”

“…1B). These results of T-cell kinetic profile and immunomodulatory effect agree with our recent study on the T-cell immunomodulatory effect of topical applied IL7-Fc in the lungs (35). Interestingly, the majority of the CD4 T cells were found in the submucosa, whereas CD8 T cells preferentially localized in the epithelium after IVAG treatment of IL7-Fc ( Supplementary Fig.…”

“…This phenomenon might be mediated by similar IL7-responsive cells residing in both the lung and genital tract. Interestingly, the lung-retentive polyclonal CD4 T cells, which were induced by IL7-Fc alone, had prophylactic effects against influenza infection (35), whereas tumor-specific CD8 T cells induced by IL7-Fc and HPV DNA vaccine played an essential role for therapeutic effects in the mucosal tumor suppression. Overall, topical IL7-Fc administration into FcRn-expressing mucosal tissues induces T-cell modulation, suggesting that the topical IL7-Fc application can be used as a mucosal adjuvant to confer protective and therapeutic immunity against virus infection at mucosal tissues.…”

Plasmacytoid Dendritic Cells Contribute to the Protective Immunity Induced by Intranasal Treatment with Fc-fused Interleukin-7 against Lethal Influenza Virus Infection

“…In a previous report, we demonstrated that a single intranasal pretreatment with Fc-fused IL-7 (IL-7-mFc) exerted protective effects against several IAV strains, which were dependent on the generation of lung-resident memory-like T cells, called T RM -like cells, by IL-7-mFc ( 15 ). Here, as a follow-up study, we investigated the cellular trafficking of IL-7-mFc-induced pulmonary T RM -like cells and potential roles of various innate immune cells in eliciting protective effects against IAVs by IL-7-mFc pretreatment.…”

Whither vaccines?

“…This may be improved in future by better understanding the role of follicular T cells in induction of protective responses, with IL-7 possibly having a role in improving persistence of protection. 83 Most pathogens have multiple virulence antigens which could be included in vaccines, and understanding the natural immune response to these, and the diff erence in responses between individuals during infection will aid antigen selection. Identifi cation of conserved epitopes may help design vaccines with 'universal' protection against a pathogen, although this has been diffi cult to achieve to date.…”